CXCR4 (C-X-C chemokine receptor type 4) variants and mutations
CXCR4 (also known as C-X-C chemokine receptor type 4) is a human protein-coding gene encoding a c-X-C chemokine receptor type 4 protein. It directs cell migration toward CXCL12 and is crucial for hematopoietic-cell homing, immune trafficking, and development. Gain-of-function variants that impair receptor desensitization cause WHIM syndrome, while tumor cells can exploit the pathway for survival and metastasis. This analysis covers 968 CXCR4 variants and mutations. Of these, 74% have computational variant effect predictions. Disease context includes WHIM syndrome, WHIM syndrome 1, and plasma cell myeloma. Example CXCR4 variants include M1?, E2*, and E2G.
Variant analysis overview
- Gene: CXCR4
- Protein: C-X-C chemokine receptor type 4
- UniProt accession: P61073
- Organism: Homo sapiens
- Variants analyzed: 968
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 654 unspecified-consequence records; 1 stop lost; 162 synonymous variants; 18 frameshift variants; 123 missense variants; 2 stop-gained variants; 5 in-frame deletions; 3 substitution
- Prediction scores: 721 variants have prediction scores (74% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: WHIM syndrome, WHIM syndrome 1, plasma cell myeloma, HIV infectious disease, non-Hodgkin lymphoma, neoplasm, lymphoma, severe congenital neutropenia, acute lymphoblastic leukemia, skin neoplasm, B-cell non-Hodgkin lymphoma, lymphoid neoplasm.
Protein structure and variant hotspots
- Protein features: 7 transmembrane segments; 20 post-translational modification sites.
- Structural context: 403 variants have structural context.
- PTM context: 52 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable CXCR4 variants
Examples include M1?, E2*, E2G, E2K, E2A, G3E, G3R, G3W. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV10502, cosmic curated COSV54018
- E2* (p.Glu2Ter), cosmic curated COSV54015
- E2G (p.Glu2Gly), rs1226785105, ClinGen CA348660418, ClinVar RCV002833797, gnomAD rs1226785105, REVEL 0.08, MetaLR 0.10, Uncertain significance
- E2K (p.Glu2Lys), cosmic curated COSV54015
- E2A (p.Glu2Ala), gnomAD 2-136118056-T-G, REVEL 0.03, MetaLR 0.09
- G3E (p.Gly3Glu), TOPMed rs1684968641, REVEL 0.04, MetaLR 0.07
- G3R (p.Gly3Arg), cosmic curated COSV54010, TOPMed rs1684968738, REVEL 0.04, AlphaMissense 0.24
- G3W (p.Gly3Trp), rs1684968738, ClinGen CA348660414, ClinVar RCV003630790, cosmic curated COSV99603, AlphaMissense 0.24, MetaLR 0.09, Likely benign
- G3G (p.Gly3Gly), gnomAD 2-136118052-C-A, CADD 9.18
- I4S (p.Ile4Ser), NCI-TCGA Cosmic COSV9960, cosmic curated COSV99603, Variant assessed as somatic; moderate impact.
- I4T (p.Ile4Thr), cosmic curated COSV10806, NCI-TCGA Cosmic COSV9960, REVEL 0.06, MetaLR 0.10, Variant assessed as somatic; moderate impact.
- I4V (p.Ile4Val), rs2104922432, ClinGen CA348660407, ClinVar RCV001968622, Ensembl rs2104922432, AlphaMissense 0.08, MetaLR 0.08, Uncertain significance
- I4I (p.Ile4Ile), rs1684968528, gnomAD 2-136118049-G-A, CADD 16.80
- I4L (p.Ile4Leu), gnomAD 2-136118051-T-G, REVEL 0.09, MetaLR 0.07
- S5C (p.Ser5Cys), Ensembl rs1684968436
- S5R (p.Ser5Arg), TOPMed rs1684968334
- p.Ser2 Leu5del, rs1184795351, gnomAD 2-136115924-GCAAA, CADD 17.90
- S5S (p.Ser5Ser), gnomAD 2-136115934-G-T, CADD 1.10
- S5G (p.Ser5Gly), rs1186182929, gnomAD 2-136115936-A-ACA, CADD 16.40
- S5P (p.Ser5Pro), rs776615103, gnomAD 2-136115936-A-G, CADD 8.72, SIFT 0.09
- S5I (p.Ser5Ile), gnomAD 2-136118047-C-A, REVEL 0.03, MetaLR 0.08
- I6T (p.Ile6Thr), TOPMed rs1684876088, gnomAD rs1684876088, REVEL 0.09, MetaLR 0.11
- I6M (p.Ile6Met), gnomAD 2-136115910-T-C, REVEL 0.11, MetaLR 0.08
- Y7C (p.Tyr7Cys), cosmic curated COSV10959, ExAC rs770986091, gnomAD rs770986091, REVEL 0.14, MetaLR 0.13
- Y7H (p.Tyr7His), rs560844176, ClinGen CA56886593, cosmic curated COSV54018, ClinVar RCV001210821, REVEL 0.03, MetaLR 0.08, Likely benign
- Y7D (p.Tyr7Asp), gnomAD 2-136115909-A-C, REVEL 0.06, MetaLR 0.09
- T8S (p.Thr8Ser), Ensembl rs2104918510, MetaLR 0.09, MetaSVM -1.00
- S9L (p.Ser9Leu), cosmic curated COSV54016, MetaLR 0.11, MetaSVM -1.05
- S9S (p.Ser9Ser), gnomAD 2-136115901-T-G, CADD 8.89
- D10N (p.Asp10Asn), cosmic curated COSV10878, MetaLR 0.12, MetaSVM -1.01
- D10V (p.Asp10Val), cosmic curated COSV10438, TOPMed rs1289282733, gnomAD rs1289282733, REVEL 0.27, MetaLR 0.21
- D10E (p.Asp10Glu), gnomAD 2-136115898-A-T, REVEL 0.10, MetaLR 0.12
- D10D (p.Asp10Asp), rs1245012855, gnomAD 2-136115898-A-G, CADD 11.20
- D10G (p.Asp10Gly), gnomAD 2-136115899-T-C, REVEL 0.25, MetaLR 0.20
- N11I (p.Asn11Ile), NCI-TCGA Cosmic COSV5401, Variant assessed as somatic; moderate impact.
- N11S (p.Asn11Ser), cosmic curated COSV54016, gnomAD rs1360006297, REVEL 0.10, MetaLR 0.14
- N11T (p.Asn11Thr), cosmic curated COSV10959
- Y12C (p.Tyr12Cys), TOPMed rs1684875253, REVEL 0.12, MetaLR 0.15
- Y12H (p.Tyr12His), cosmic curated COSV54014
- Y12Y (p.Tyr12Tyr), rs1423911335, gnomAD 2-136115892-G-A, CADD 8.32
- T13A (p.Thr13Ala), ExAC rs762966305, gnomAD rs762966305, REVEL 0.08, MetaLR 0.12
- T13T (p.Thr13Thr), rs375868851, gnomAD 2-136115889-G-C, CADD 0.84
- T13S (p.Thr13Ser), gnomAD 2-136115890-G-C, REVEL 0.17, MetaLR 0.12
- E14K (p.Glu14Lys), rs1558837039, NCI-TCGA Cosmic COSV5401, cosmic curated COSV54012, Ensembl rs1558837039, REVEL 0.15, MetaLR 0.14, Variant assessed as somatic; moderate impact.
- E14V (p.Glu14Val), gnomAD rs1360656571, REVEL 0.10, MetaLR 0.13
- E15K (p.Glu15Lys), cosmic curated COSV10452
- E15del (p.Glu15del), gnomAD 2-136115883-TTCC-, CADD 18.90
- M16I (p.Met16Ile), cosmic curated COSV99603
- M16K (p.Met16Lys), TOPMed rs1684874344, MetaLR 0.12, MetaSVM -1.00
- M16T (p.Met16Thr), gnomAD 2-136115881-A-G, REVEL 0.08, MetaLR 0.11
- G17C (p.Gly17Cys), cosmic curated COSV54010
- G17D (p.Gly17Asp), rs770327175, NCI-TCGA Cosmic COSV9960, cosmic curated COSV99602, ExAC rs770327175, REVEL 0.08, MetaLR 0.15, Variant assessed as somatic; moderate impact.
- G17V (p.Gly17Val), ExAC rs770327175, TOPMed rs770327175, gnomAD rs770327175, MetaLR 0.20, MetaSVM -0.71
- G17G (p.Gly17Gly), gnomAD 2-136115877-G-T, CADD 6.46
- S18* (p.Ser18Ter), NCI-TCGA Cosmic COSV5401, cosmic curated COSV54013, Variant assessed as somatic; high impact.
- S18L (p.Ser18Leu), gnomAD rs1363377230, REVEL 0.18, MetaLR 0.12
- S18S (p.Ser18Ser), gnomAD 2-136115874-T-C, CADD 1.15
- G19E (p.Gly19Glu), NCI-TCGA Cosmic COSV5401, cosmic curated COSV54016, TOPMed rs1684873595, Variant assessed as somatic; moderate impact.
- G19V (p.Gly19Val), cosmic curated COSV54017
- G19W (p.Gly19Trp), NCI-TCGA Cosmic COSV5401, cosmic curated COSV54010, Variant assessed as somatic; moderate impact.
- D20D (p.Asp20Asp), gnomAD 2-136115868-G-A, CADD 12.00
- D20H (p.Asp20His), gnomAD 2-136115870-C-G, REVEL 0.32, MetaLR 0.30
- Y21C (p.Tyr21Cys), cosmic curated COSV54012, MetaLR 0.24, MetaSVM -0.65
- Y21S (p.Tyr21Ser), gnomAD 2-136115866-T-G, REVEL 0.20, MetaLR 0.16
- Y21D (p.Tyr21Asp), gnomAD 2-136115867-A-C, REVEL 0.08, MetaLR 0.15
- D22G (p.Asp22Gly), gnomAD 2-136115863-T-C, REVEL 0.03, MetaLR 0.12
- D22M (p.Asp22Met), gnomAD 2-136115864-C-CAT, CADD 26.90
- S23P (p.Ser23Pro), ExAC rs748493255, gnomAD rs748493255, REVEL 0.12, MetaLR 0.12
- S23Y (p.Ser23Tyr), NCI-TCGA TCGA novel, MetaLR 0.09, MetaSVM -1.07, Variant assessed as somatic; moderate impact.
- S23S (p.Ser23Ser), rs781598359, gnomAD 2-136115859-G-T, CADD 13.00
- S23F (p.Ser23Phe), gnomAD 2-136115860-G-A, REVEL 0.02, MetaLR 0.09
- M24I (p.Met24Ile), cosmic curated COSV54013, NCI-TCGA Cosmic COSV5401, cosmic curated COSV54011, Variant assessed as somatic; moderate impact.
- M24V (p.Met24Val), rs1684873120, ClinGen CA348660205, ClinVar RCV003515696, TOPMed rs1684873120, AlphaMissense 0.07, MetaLR 0.09, Uncertain significance
- K25R (p.Lys25Arg), rs1387554691, gnomAD rs1387554691, REVEL 0.03, MetaLR 0.12, Variant assessed as somatic; moderate impact.
- E26K (p.Glu26Lys), NCI-TCGA Cosmic COSV5401, cosmic curated COSV54010, Variant assessed as somatic; moderate impact.
- E26V (p.Glu26Val), cosmic curated COSV54011, MetaLR 0.23, MetaSVM -0.69
- P27H (p.Pro27His), gnomAD 2-136115923-G-T, CADD 22.70, SIFT 0.04
- P27R (p.Pro27Arg), rs759904341, gnomAD 2-136115929-G-C, CADD 15.80, SIFT 0.20
- P27L (p.Pro27Leu), rs759904341, gnomAD 2-136115929-G-A, CADD 16.00, SIFT 0.99
- P27A (p.Pro27Ala), rs767838620, gnomAD 2-136115930-G-C, CADD 11.70, SIFT 0.67
- C28G (p.Cys28Gly), cosmic curated COSV54009
- C28R (p.Cys28Arg), TOPMed rs1684872844
- C28S (p.Cys28Ser), NCI-TCGA Cosmic COSV5400, REVEL 0.40, MetaLR 0.17, Variant assessed as somatic; moderate impact.
- F29F (p.Phe29Phe), rs768296315, gnomAD 2-136115841-G-A, CADD 13.00
- R30C (p.Arg30Cys), cosmic curated COSV54010, REVEL 0.17, MetaLR 0.12
- R30H (p.Arg30His), rs923351521, ClinGen CA56886585, cosmic curated COSV54013, ClinVar RCV003628842, REVEL 0.13, MetaLR 0.06, Uncertain significance
- R30L (p.Arg30Leu), cosmic curated COSV54011, TOPMed rs923351521, gnomAD rs923351521, MetaLR 0.05, MetaSVM -1.07, Uncertain significance
- R30P (p.Arg30Pro), gnomAD 2-136115839-C-G, REVEL 0.12, MetaLR 0.05
- E31G (p.Glu31Gly), cosmic curated COSV10727, MetaLR 0.06, MetaSVM -1.06
- E32A (p.Glu32Ala), TOPMed rs1684872314, REVEL 0.04, MetaLR 0.05
- N33H (p.Asn33His), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- N33I (p.Asn33Ile), rs1230454603, ClinGen CA348660132, ClinVar RCV004367602, TOPMed rs1230454603, REVEL 0.08, MetaLR 0.09, Uncertain significance
- N33T (p.Asn33Thr), cosmic curated COSV54011, MetaLR 0.05, MetaSVM -1.07
- N33N (p.Asn33Asn), rs184978014, gnomAD 2-136115829-A-G, CADD 9.18
- N35D (p.Asn35Asp), rs779590491, ClinGen CA1890159, ClinVar RCV003872562, ExAC rs779590491, REVEL 0.04, MetaLR 0.04, Uncertain significance
- N35T (p.Asn35Thr), TOPMed rs1684872213, MetaLR 0.06, MetaSVM -1.06
- F36C (p.Phe36Cys), Ensembl rs1684872067
- F36S (p.Phe36Ser), cosmic curated COSV10727, MetaLR 0.19, MetaSVM -0.76
- N37D (p.Asn37Asp), rs757881953, ClinGen CA1890158, ClinVar RCV003870177, ExAC rs757881953, REVEL 0.07, MetaLR 0.08, Uncertain significance
- N37S (p.Asn37Ser), rs749938835, ClinGen CA1890157, ClinVar RCV002010777, ClinVar RCV005542672, REVEL 0.06, MetaLR 0.06, Uncertain significance
- N37Y (p.Asn37Tyr), cosmic curated COSV54013
- K38* (p.Lys38Ter), cosmic curated COSV10502
- I39M (p.Ile39Met), cosmic curated COSV54011
- I39T (p.Ile39Thr), rs1684871649, ClinGen CA348660090, ClinVar RCV003628689, TOPMed rs1684871649, AlphaMissense 0.45, MetaLR 0.12, Uncertain significance
- F40F (p.Phe40Phe), gnomAD 2-136115808-G-A, CADD 11.70
- F40V (p.Phe40Val), gnomAD 2-136115810-A-C, REVEL 0.66, MetaLR 0.18
- L41L (p.Leu41Leu), rs1684871563, gnomAD 2-136115805-C-A, CADD 12.30
- L41V (p.Leu41Val), rs1485584805, gnomAD 2-136115921-G-C, CADD 16.30, SIFT 0.60
- L41* (p.Leu41Ter), rs1053292586, gnomAD 2-136115926-A-T, CADD 36.00
- P42R (p.Pro42Arg), gnomAD rs1268474896, REVEL 0.74, MetaLR 0.30
- P42S (p.Pro42Ser), cosmic curated COSV99603, MetaLR 0.30, MetaSVM -0.37
- P42L (p.Pro42Leu), gnomAD 2-136115803-G-A, REVEL 0.68, MetaLR 0.24
- T43A (p.Thr43Ala), gnomAD rs1221387101, REVEL 0.11, MetaLR 0.06
- T43I (p.Thr43Ile), cosmic curated COSV54011, MetaLR 0.09, MetaSVM -1.10
- T43N (p.Thr43Asn), ExAC rs778969048, TOPMed rs778969048, gnomAD rs778969048, REVEL 0.19, MetaLR 0.25
- T43S (p.Thr43Ser), ExAC rs778969048, TOPMed rs778969048, gnomAD rs778969048, REVEL 0.07, MetaLR 0.08
- T43T (p.Thr43Thr), rs1684871135, gnomAD 2-136115799-G-A, CADD 9.41
- I44M (p.Ile44Met), NCI-TCGA TCGA novel, MetaLR 0.03, MetaSVM -1.06, Variant assessed as somatic; moderate impact.
- I44V (p.Ile44Val), TOPMed rs1267066087, gnomAD rs1267066087, REVEL 0.02, MetaLR 0.03
- S46C (p.Ser46Cys), rs147467366, ClinGen CA1890155, ClinVar RCV001819628, ClinVar RCV001869705, REVEL 0.09, MetaLR 0.10, Uncertain significance
- I47I (p.Ile47Ile), gnomAD 2-136115787-G-A, CADD 13.50
- I48V (p.Ile48Val), TOPMed rs1359102217, gnomAD rs1359102217, REVEL 0.13, MetaLR 0.08
- F49F (p.Phe49Phe), rs1684870541, gnomAD 2-136115781-G-A, CADD 12.50
- L50S (p.Leu50Ser), Ensembl rs1241516977
- L50V (p.Leu50Val), ExAC rs753680989, gnomAD rs753680989, REVEL 0.03, MetaLR 0.05
- T51I (p.Thr51Ile), cosmic curated COSV10502, NCI-TCGA TCGA novel, MetaLR 0.04, MetaSVM -1.03, Variant assessed as somatic; moderate impact.
- T51T (p.Thr51Thr), rs145879963, gnomAD 2-136115775-A-T, CADD 11.80
- T51P (p.Thr51Pro), gnomAD 2-136115777-T-G, REVEL 0.15, MetaLR 0.10
- T51S (p.Thr51Ser), gnomAD 2-136115777-T-A, REVEL 0.02, MetaLR 0.06
- G52V (p.Gly52Val), cosmic curated COSV54009, MetaLR 0.43, MetaSVM 0.02
- I53L (p.Ile53Leu), rs56400844, ClinGen CA1890152, ClinVar RCV000880790, ClinVar RCV001357354, REVEL 0.06, MetaLR 0.05, Benign
- I53T (p.Ile53Thr), gnomAD rs1343187033
- I53V (p.Ile53Val), cosmic curated COSV99603, 1000Genomes rs56400844, ESP rs56400844, ExAC rs56400844, MetaLR 0.07, MetaSVM -0.82, Benign
- I53I (p.Ile53Ile), gnomAD 2-136115769-A-G, CADD 8.52
- V54L (p.Val54Leu), cosmic curated COSV10959
- V54V (p.Val54Val), rs1684869342, gnomAD 2-136115766-C-T, CADD 10.70
- V54M (p.Val54Met), gnomAD 2-136115768-C-T, REVEL 0.07, MetaLR 0.08
- G55A (p.Gly55Ala), cosmic curated COSV10727
- G55D (p.Gly55Asp), cosmic curated COSV10438
- G55V (p.Gly55Val), Ensembl rs1684869258, MetaLR 0.47, MetaSVM 0.07
- G55G (p.Gly55Gly), rs1302147452, gnomAD 2-136115763-G-T, CADD 10.90
- N56D (p.Asn56Asp), ExAC rs751756723, gnomAD rs751756723, REVEL 0.95, MetaLR 0.96
- N56S (p.Asn56Ser), TOPMed rs1393307051, gnomAD rs1393307051, REVEL 0.94, MetaLR 0.96
- N56N (p.Asn56Asn), rs1684868879, gnomAD 2-136115760-A-G, CADD 10.70
- G57E (p.Gly57Glu), cosmic curated COSV10438
- G57R (p.Gly57Arg), cosmic curated COSV54016
- G57G (p.Gly57Gly), rs533290861, gnomAD 2-136115757-T-C, CADD 11.20
- G57V (p.Gly57Val), gnomAD 2-136115758-C-A, REVEL 0.18, MetaLR 0.16
- L58F (p.Leu58Phe), cosmic curated COSV54010
- V59I (p.Val59Ile), rs1314188521, ClinGen CA348659966, ClinVar RCV003225902, AlphaMissense 0.92, MetaLR 0.70, Uncertain significance
- V59L (p.Val59Leu), gnomAD rs1314188521, REVEL 0.63, AlphaMissense 0.92
- V59V (p.Val59Val), gnomAD 2-136115751-G-T, CADD 9.90
- I60N (p.Ile60Asn), gnomAD rs1374176769, REVEL 0.81, MetaLR 0.68
- I60V (p.Ile60Val), ExAC rs763059810, gnomAD rs763059810, REVEL 0.10, MetaLR 0.15
- I60I (p.Ile60Ile), rs1684868295, gnomAD 2-136115748-G-T, CADD 11.30
- L61M (p.Leu61Met), cosmic curated COSV54010
- L61L (p.Leu61Leu), rs1641947845, gnomAD 2-136115745-C-T, CADD 11.20
- L61V (p.Leu61Val), gnomAD 2-136115747-G-C, REVEL 0.04, MetaLR 0.05
- V62I (p.Val62Ile), rs2467266454, ClinGen CA348659949, ClinVar RCV002999849, Likely benign
- V62V (p.Val62Val), rs1484355680, gnomAD 2-136115742-G-A, CADD 10.10
- M63I (p.Met63Ile), cosmic curated COSV54010, MetaLR 0.03, MetaSVM -1.05
- M63T (p.Met63Thr), rs773216142, ClinGen CA1890148, ClinVar RCV003876367, ClinVar RCV005555078, REVEL 0.42, MetaLR 0.11, Likely benign
- M63V (p.Met63Val), gnomAD 2-136115741-T-C, REVEL 0.13, MetaLR 0.05
- G64A (p.Gly64Ala), gnomAD rs1479506035, REVEL 0.16, MetaLR 0.14
- G64G (p.Gly64Gly), gnomAD 2-136115736-A-C, CADD 13.20
- Q66* (p.Gln66Ter), cosmic curated COSV10727
- Q66R (p.Gln66Arg), rs1428775677, gnomAD rs1428775677, REVEL 0.45, MetaLR 0.32, Variant assessed as somatic; moderate impact.
- Q66Q (p.Gln66Gln), rs770275656, gnomAD 2-136115730-C-T, CADD 12.90
- K67N (p.Lys67Asn), cosmic curated COSV54018, NCI-TCGA Cosmic COSV5401, MetaLR 0.18, MetaSVM -0.77, Variant assessed as somatic; moderate impact.
- K68Q (p.Lys68Gln), TOPMed rs1481575745, gnomAD rs1481575745, REVEL 0.57, MetaLR 0.48
- L69P (p.Leu69Pro), cosmic curated COSV99602
- L69Q (p.Leu69Gln), ExAC rs762377247, gnomAD rs762377247, REVEL 0.07, MetaLR 0.08
- L69R (p.Leu69Arg), ExAC rs762377247, gnomAD rs762377247
- L69L (p.Leu69Leu), gnomAD 2-136115721-C-T, CADD 9.75
- L69V (p.Leu69Val), rs889949060, []
- S71G (p.Ser71Gly), Ensembl rs1684867249
- S71N (p.Ser71Asn), Ensembl rs1046266103, MetaLR 0.10, MetaSVM -1.06
- M72K (p.Met72Lys), gnomAD 2-136115713-A-T, REVEL 0.41, MetaLR 0.17
- T73M (p.Thr73Met), TOPMed rs943396331, REVEL 0.59, MetaLR 0.28
- T73T (p.Thr73Thr), rs909200339, gnomAD 2-136115709-C-T, CADD 2.37
Public CXCR4 analysis runs
- CXCR4 analysis run — CXCR4 (968 variants) — completed 2026-08-18