EPHA3 (Ephrin type-A receptor 3) variants and mutations
EPHA3 (also known as Ephrin type-A receptor 3) is a human protein-coding gene encoding an ephrin type-A receptor 3 protein. Its annotated function is receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the…. It is annotated at the cell membrane. This analysis covers 2,675 EPHA3 variants and mutations. Of these, 46% have computational variant effect predictions. Disease context includes medullary thyroid gland carcinoma, neurodegenerative disease, and atrial fibrillation. Example EPHA3 variants include M1?, D2A, and D2E.
Variant analysis overview
- Gene: EPHA3
- Protein: Ephrin type-A receptor 3
- UniProt accession: P29320
- Organism: Homo sapiens
- Variants analyzed: 2675
- Variant scope: all variants
- Completed: 2026-09-01
Variant and mutation evidence
- Variant composition: 2,433 unspecified-consequence records; 106 missense variants; 5 frameshift variants; 125 synonymous variants; 6 in-frame deletions; 1 in-frame insertions; 2 stop-gained variants; 1 splice-region variants
- Prediction scores: 1,221 variants have prediction scores (46% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: medullary thyroid gland carcinoma, neurodegenerative disease, atrial fibrillation, neoplasm, non-small cell lung carcinoma, thyroid gland carcinoma, venous thromboembolism, pulmonary embolism, Pulmonary Infarction, thyroid tumor, ovarian dysfunction, alcohol drinking.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 5 domains; 4 binding sites; 10 post-translational modification sites.
- Structural context: 2,044 variants have structural context.
- PTM context: 19 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 EPHA3 variants
Examples include M1?, D2A, D2E, D2H, D2N, D2V, D2Y, C3*. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA Cosmic COSV6072, Variant assessed as somatic; high impact.
- D2A (p.Asp2Ala), TOPMed rs1707005525, REVEL 0.29, CADD 25.10
- D2E (p.Asp2Glu), Ensembl rs2106932130
- D2H (p.Asp2His), ExAC rs770282917, gnomAD rs770282917
- D2N (p.Asp2Asn), NCI-TCGA Cosmic COSV6070, cosmic curated COSV60705, ExAC rs770282917, gnomAD rs770282917, Variant assessed as somatic; moderate impact.
- D2V (p.Asp2Val), cosmic curated COSV10590, TOPMed rs1707005525
- D2Y (p.Asp2Tyr), ExAC rs770282917, gnomAD rs770282917, REVEL 0.30, CADD 29.40
- C3* (p.Cys3Ter), Ensembl rs2106932150
- C3G (p.Cys3Gly), ExAC rs775889890, gnomAD rs775889890, REVEL 0.30, CADD 22.60
- C3S (p.Cys3Ser), ExAC rs775889890, gnomAD rs775889890
- C3R (p.Cys3Arg), gnomAD 3-89107755-T-C, REVEL 0.18, CADD 23.20
- C3W (p.Cys3Trp), gnomAD 3-89107755-T-TG, CADD 32.00
- Q4* (p.Gln4Ter), cosmic curated COSV10815, Ensembl rs2106932157
- Q4E (p.Gln4Glu), Ensembl rs2106932157, REVEL 0.14, CADD 19.50
- Q4H (p.Gln4His), Ensembl rs2106932177
- Q4L (p.Gln4Leu), Ensembl rs2106932169
- Q4R (p.Gln4Arg), gnomAD 3-89107759-A-G, REVEL 0.14, CADD 21.60
- Q4Q (p.Gln4Gln), rs2106932177, gnomAD 3-89107760-G-A, CADD 9.86
- L5I (p.Leu5Ile), Ensembl rs2106932182
- L5P (p.Leu5Pro), cosmic curated COSV60694, Ensembl rs2106932192
- L5V (p.Leu5Val), Ensembl rs2106932182
- S6A (p.Ser6Ala), Ensembl rs1707005715, REVEL 0.13, CADD 17.60
- S6C (p.Ser6Cys), ExAC rs764355602, TOPMed rs764355602, gnomAD rs764355602
- S6F (p.Ser6Phe), ExAC rs764355602, TOPMed rs764355602, gnomAD rs764355602, REVEL 0.10, CADD 23.40
- S6P (p.Ser6Pro), cosmic curated COSV10590, Ensembl rs1707005715, REVEL 0.21, CADD 22.50
- S6T (p.Ser6Thr), Ensembl rs1707005715
- S6Y (p.Ser6Tyr), cosmic curated COSV60699, ExAC rs764355602, TOPMed rs764355602, gnomAD rs764355602, REVEL 0.10, CADD 23.10
- I7L (p.Ile7Leu), ExAC rs751989411, REVEL 0.07, CADD 13.40
- I7M (p.Ile7Met), ExAC rs761960062, gnomAD rs761960062
- I7T (p.Ile7Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- I7V (p.Ile7Val), gnomAD 3-89107767-A-G, REVEL 0.05, CADD 10.40
- I7I (p.Ile7Ile), rs761960062, gnomAD 3-89107769-C-T, CADD 11.30
- L8F (p.Leu8Phe), ExAC rs750454214, gnomAD rs750454214, REVEL 0.07, CADD 17.00
- L8H (p.Leu8His), Ensembl rs2106932281
- L8I (p.Leu8Ile), ExAC rs750454214, gnomAD rs750454214
- L8P (p.Leu8Pro), Ensembl rs2106932281
- L8L (p.Leu8Leu), rs747897732, gnomAD 3-89107772-C-T, CADD 9.38
- L9F (p.Leu9Phe), cosmic curated COSV10034, Ensembl rs1707006339, REVEL 0.04, CADD 11.70
- L9I (p.Leu9Ile), Ensembl rs1707006339, REVEL 0.02, CADD 10.90
- L9P (p.Leu9Pro), Ensembl rs2106932320
- L9L (p.Leu9Leu), rs1707006410, gnomAD 3-89107775-C-G, CADD 7.60
- L10F (p.Leu10Phe), cosmic curated COSV60726, ExAC rs771405440, TOPMed rs771405440, gnomAD rs771405440, REVEL 0.06, CADD 15.40
- L10P (p.Leu10Pro), Ensembl rs2106932354
- L10V (p.Leu10Val), ExAC rs771405440, TOPMed rs771405440, gnomAD rs771405440
- L10L (p.Leu10Leu), rs1194230707, gnomAD 3-89107778-T-C, CADD 2.60
- L11F (p.Leu11Phe), Ensembl rs2106932363
- L11del (p.Leu11del), rs768142526, gnomAD 3-89107767-ATCC-A, CADD 16.70
- p.Leu11dup, gnomAD 3-89107767-A-ATCC, CADD 17.30
- L11L (p.Leu11Leu), rs1250832742, gnomAD 3-89107781-C-A, CADD 9.08
- S12C (p.Ser12Cys), Ensembl rs1707006783
- S12G (p.Ser12Gly), Ensembl rs1707006783, REVEL 0.04, CADD 13.10
- S12T (p.Ser12Thr), Ensembl rs2106932389
- C13F (p.Cys13Phe), Ensembl rs2106932414
- C13S (p.Cys13Ser), Ensembl rs2106932414, REVEL 0.05, CADD 14.50
- C13Y (p.Cys13Tyr), cosmic curated COSV60727, Ensembl rs2106932414
- C13del (p.Cys13del), gnomAD 3-89107782-AGCT-A, CADD 17.80
- S14F (p.Ser14Phe), ExAC rs369721497, gnomAD rs369721497, REVEL 0.14, CADD 17.10
- S14P (p.Ser14Pro), ExAC rs780224889, TOPMed rs780224889, gnomAD rs780224889, REVEL 0.07, CADD 21.00
- S14T (p.Ser14Thr), ExAC rs780224889, TOPMed rs780224889, gnomAD rs780224889
- S14Y (p.Ser14Tyr), ExAC rs369721497, gnomAD rs369721497, REVEL 0.12, CADD 14.70
- S14C (p.Ser14Cys), gnomAD 3-89107789-C-G, REVEL 0.12, CADD 19.00
- S14S (p.Ser14Ser), gnomAD 3-89107790-T-C, CADD 4.82
- V15A (p.Val15Ala), ExAC rs758417906, gnomAD rs758417906, REVEL 0.15, CADD 2.81
- V15D (p.Val15Asp), ExAC rs758417906, gnomAD rs758417906
- V15F (p.Val15Phe), Ensembl rs373387079, REVEL 0.03, CADD 2.59
- V15G (p.Val15Gly), ExAC rs758417906, gnomAD rs758417906
- V15I (p.Val15Ile), Ensembl rs373387079
- V15L (p.Val15Leu), Ensembl rs373387079
- L16F (p.Leu16Phe), Ensembl rs1707007423
- L16H (p.Leu16His), Ensembl rs2106932482
- L16I (p.Leu16Ile), NCI-TCGA Cosmic COSV1003, NCI-TCGA Cosmic COSV6072, cosmic curated COSV60728, REVEL 0.04, CADD 13.90, Variant assessed as somatic; moderate impact.
- L16V (p.Leu16Val), NCI-TCGA Cosmic COSV1003, cosmic curated COSV10034, NCI-TCGA Cosmic COSV6072, Ensembl rs1707007423, REVEL 0.04, CADD 13.40, Variant assessed as somatic; moderate impact.
- L16L (p.Leu16Leu), rs1191363765, gnomAD 3-89107796-C-G, CADD 7.15
- D17A (p.Asp17Ala), gnomAD rs1461534861
- D17E (p.Asp17Glu), TOPMed rs1194741028, gnomAD rs1194741028, REVEL 0.04, CADD 6.96
- D17G (p.Asp17Gly), gnomAD rs1461534861, REVEL 0.05, CADD 2.21
- D17H (p.Asp17His), rs201110271, ClinGen CA2502202, ClinVar RCV004239144, 1000Genomes rs201110271, REVEL 0.04, CADD 0.01, Uncertain significance, not specified
- D17N (p.Asp17Asn), 1000Genomes rs201110271, ExAC rs201110271, TOPMed rs201110271, gnomAD rs201110271, REVEL 0.04, CADD 0.00, Uncertain significance
- D17V (p.Asp17Val), gnomAD rs1461534861
- D17Y (p.Asp17Tyr), 1000Genomes rs201110271, ExAC rs201110271, TOPMed rs201110271, gnomAD rs201110271, REVEL 0.06, CADD 0.14, Uncertain significance
- S18G (p.Ser18Gly), TOPMed rs1480670631, gnomAD rs1480670631
- S18N (p.Ser18Asn), Ensembl rs2106932535
- S18R (p.Ser18Arg), Ensembl rs2106932540, cosmic curated COSV60695, REVEL 0.06, CADD 11.80
- F19L (p.Phe19Leu), Ensembl rs1559734115, REVEL 0.05, CADD 12.90
- F19F (p.Phe19Phe), rs746804156, gnomAD 3-89107805-C-T, CADD 8.96
- G20A (p.Gly20Ala), Ensembl rs2106932572
- G20E (p.Gly20Glu), Ensembl rs2106932572, REVEL 0.14, CADD 21.60
- G20R (p.Gly20Arg), Ensembl rs2106932563, cosmic curated COSV60731
- G20V (p.Gly20Val), cosmic curated COSV60723, Ensembl rs2106932572
- G20W (p.Gly20Trp), NCI-TCGA Cosmic COSV6073, Ensembl rs2106932563, Variant assessed as somatic; moderate impact.
- E21D (p.Glu21Asp), NCI-TCGA Cosmic COSV1003, cosmic curated COSV10034, Ensembl rs2106932609, Variant assessed as somatic; moderate impact.
- E21K (p.Glu21Lys), 1000Genomes rs141456190, ESP rs141456190, ExAC rs141456190, TOPMed rs141456190, REVEL 0.12, CADD 19.70, Uncertain significance, not specified
- E21Q (p.Glu21Gln), 1000Genomes rs141456190, ESP rs141456190, ExAC rs141456190, TOPMed rs141456190, Uncertain significance
- L22M (p.Leu22Met), NCI-TCGA Cosmic COSV1003, cosmic curated COSV10034, Ensembl rs2106932614, Variant assessed as somatic; moderate impact.
- L22P (p.Leu22Pro), Ensembl rs2106932625
- L22V (p.Leu22Val), Ensembl rs2106932614
- I23F (p.Ile23Phe), Ensembl rs2106932643
- I23M (p.Ile23Met), Ensembl rs2106932659
- I23S (p.Ile23Ser), Ensembl rs2106932649, REVEL 0.06, CADD 0.05
- P24A (p.Pro24Ala), cosmic curated COSV60716, Ensembl rs2106932666
- P24L (p.Pro24Leu), rs1433031247, gnomAD rs1433031247, REVEL 0.06, CADD 8.51, Variant assessed as somatic; moderate impact.
- P24R (p.Pro24Arg), gnomAD rs1433031247
- P24S (p.Pro24Ser), Ensembl rs2106932666
- P24P (p.Pro24Pro), rs200437524, gnomAD 3-89107820-G-T, CADD 4.85
- Q25* (p.Gln25Ter), TOPMed rs1236884924
- Q25H (p.Gln25His), Ensembl rs759455117
- Q25K (p.Gln25Lys), TOPMed rs1236884924
- Q25L (p.Gln25Leu), Ensembl rs2106932699
- P26A (p.Pro26Ala), TOPMed rs1341481107, gnomAD rs1341481107, REVEL 0.14, CADD 23.30
- P26H (p.Pro26His), Ensembl rs1707009309
- P26L (p.Pro26Leu), Ensembl rs1707009309, REVEL 0.22, CADD 24.60
- P26S (p.Pro26Ser), TOPMed rs1341481107, gnomAD rs1341481107, REVEL 0.13, CADD 23.70
- P26T (p.Pro26Thr), gnomAD 3-89107824-C-A, REVEL 0.19, CADD 23.60
- S27C (p.Ser27Cys), cosmic curated COSV60718, Ensembl rs2106932747
- S27F (p.Ser27Phe), cosmic curated COSV60701, Ensembl rs2106932747
- S27S (p.Ser27Ser), gnomAD 3-89107829-C-T, CADD 14.00
- N28D (p.Asn28Asp), Ensembl rs1559734152, REVEL 0.13, CADD 24.90
- N28K (p.Asn28Lys), Ensembl rs2106932773, REVEL 0.08, CADD 22.50
- N28S (p.Asn28Ser), ExAC rs745339448, TOPMed rs745339448, gnomAD rs745339448, REVEL 0.12, CADD 24.00
- N28Y (p.Asn28Tyr), gnomAD 3-89107830-A-T, REVEL 0.32, CADD 28.50
- E29G (p.Glu29Gly), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- E29K (p.Glu29Lys), cosmic curated COSV60694, Ensembl rs2106932783, REVEL 0.18, CADD 25.10
- E29Q (p.Glu29Gln), Ensembl rs2106932783
- E29* (p.Glu29Ter), gnomAD 3-89107833-G-T, CADD 39.00
- V30A (p.Val30Ala), gnomAD rs1347546355, REVEL 0.18, CADD 24.60
- V30I (p.Val30Ile), gnomAD 3-89107836-G-A, REVEL 0.20, CADD 34.00
- N31D (p.Asn31Asp), gnomAD rs1157209705, REVEL 0.16, CADD 24.90
- N31K (p.Asn31Lys), gnomAD 3-89127213-T-A, REVEL 0.16, CADD 26.00
- N31N (p.Asn31Asn), rs1704113620, gnomAD 3-89127213-T-C, CADD 10.30
- L32L (p.Leu32Leu), rs773685257, gnomAD 3-89127216-A-C, CADD 0.64
- L33R (p.Leu33Arg), NCI-TCGA Cosmic COSV6072, cosmic curated COSV60729, Variant assessed as somatic; moderate impact.
- D34H (p.Asp34His), NCI-TCGA Cosmic COSV6073, Variant assessed as somatic; moderate impact.
- D34D (p.Asp34Asp), rs1458762152, gnomAD 3-89127222-T-C, CADD 10.50
- S35L (p.Ser35Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K36E (p.Lys36Glu), cosmic curated COSV10590, TOPMed rs1704113845
- T37A (p.Thr37Ala), cosmic curated COSV60696, TOPMed rs1321323037, gnomAD rs1321323037, REVEL 0.12, CADD 18.10
- T37K (p.Thr37Lys), UniProt VAR 036086, Uncertain significance, in a colorectal cancer sample
- I38V (p.Ile38Val), gnomAD rs1295767981, REVEL 0.06, CADD 15.10
- Q39E (p.Gln39Glu), ExAC rs760801471, TOPMed rs760801471, gnomAD rs760801471, REVEL 0.21, CADD 22.80
- Q39K (p.Gln39Lys), rs760801471, NCI-TCGA Cosmic COSV6070, ExAC rs760801471, TOPMed rs760801471, REVEL 0.20, CADD 23.90, Variant assessed as somatic; moderate impact.
- Q39Q (p.Gln39Gln), rs766626719, gnomAD 3-89127237-A-G, CADD 13.10
- G40V (p.Gly40Val), NCI-TCGA Cosmic COSV6070, NCI-TCGA Cosmic COSV6071, cosmic curated COSV60711, Variant assessed as somatic; moderate impact.
- G40W (p.Gly40Trp), gnomAD 3-89127238-G-T, REVEL 0.54, CADD 28.40
- G40G (p.Gly40Gly), rs1704114111, gnomAD 3-89127240-G-A, CADD 9.53
- E41* (p.Glu41Ter), ESP rs374211029, ExAC rs374211029, TOPMed rs374211029, gnomAD rs374211029, CADD 41.00
- E41K (p.Glu41Lys), cosmic curated COSV10590, ESP rs374211029, ExAC rs374211029, TOPMed rs374211029, REVEL 0.50, CADD 27.50
- E41Q (p.Glu41Gln), gnomAD 3-89127241-G-C, REVEL 0.38, CADD 25.90
- L42P (p.Leu42Pro), TOPMed rs756018331, gnomAD rs756018331, REVEL 0.50, CADD 27.90
- L42L (p.Leu42Leu), rs759710031, gnomAD 3-89127244-C-T, CADD 10.30
- G43A (p.Gly43Ala), ESP rs372273179, ExAC rs372273179, TOPMed rs372273179, gnomAD rs372273179, REVEL 0.29, CADD 24.10
- G43D (p.Gly43Asp), ESP rs372273179, ExAC rs372273179, TOPMed rs372273179, gnomAD rs372273179
- G43S (p.Gly43Ser), ESP rs368633855, TOPMed rs368633855, gnomAD rs368633855, REVEL 0.41, CADD 27.10
- I45F (p.Ile45Phe), NCI-TCGA TCGA novel, TOPMed rs1704114496, REVEL 0.24, CADD 25.80, Variant assessed as somatic; moderate impact.
- I45M (p.Ile45Met), rs139262347, ClinGen CA2502237, ClinVar RCV004252293, 1000Genomes rs139262347, REVEL 0.16, CADD 22.80, Uncertain significance, not specified
- I45N (p.Ile45Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- I45V (p.Ile45Val), gnomAD 3-89127253-A-G, REVEL 0.21, CADD 23.80
- I45I (p.Ile45Ile), rs139262347, gnomAD 3-89127255-C-T, CADD 10.60
- S46C (p.Ser46Cys), rs1559743082, NCI-TCGA Cosmic COSV6069, cosmic curated COSV60696, Ensembl rs1559743082, AlphaMissense 0.33, MetaLR 0.05, Variant assessed as somatic; moderate impact.
- S46A (p.Ser46Ala), gnomAD 3-89127256-T-G, REVEL 0.24, CADD 23.20
- S46Y (p.Ser46Tyr), gnomAD 3-89127257-C-A, REVEL 0.32, CADD 25.50
- S46S (p.Ser46Ser), gnomAD 3-89127258-T-G, CADD 8.79
- Y47Y (p.Tyr47Tyr), rs950929609, gnomAD 3-89127261-T-C, CADD 3.67
- P48S (p.Pro48Ser), NCI-TCGA Cosmic COSV6069, cosmic curated COSV60698, NCI-TCGA Cosmic COSV6072, REVEL 0.27, CADD 24.90, Variant assessed as somatic; moderate impact.
- P48T (p.Pro48Thr), NCI-TCGA Cosmic COSV6069, NCI-TCGA Cosmic COSV6072, Variant assessed as somatic; moderate impact.
- P48P (p.Pro48Pro), rs1246784896, gnomAD 3-89127264-A-G, CADD 7.96
- S49L (p.Ser49Leu), gnomAD rs1559743096, REVEL 0.10, CADD 23.00
- S49S (p.Ser49Ser), gnomAD 3-89127267-A-T, CADD 5.84
- H50N (p.His50Asn), TOPMed rs993037877, gnomAD rs993037877, REVEL 0.31, CADD 22.40
- H50R (p.His50Arg), TOPMed rs1468754976, gnomAD rs1468754976, REVEL 0.29, CADD 23.30
- H50Y (p.His50Tyr), gnomAD 3-89127268-C-T, REVEL 0.28, CADD 25.10
- H50L (p.His50Leu), gnomAD 3-89127269-A-T, REVEL 0.33, CADD 23.90
- H50H (p.His50His), rs767404825, gnomAD 3-89127270-T-C, CADD 7.03
- H50Q (p.His50Gln), gnomAD 3-89127270-T-A, REVEL 0.23, CADD 20.40
- G51=, NCI-TCGA Cosmic COSV6070, Variant assessed as somatic; low impact.
- G51R (p.Gly51Arg), cosmic curated COSV10740, ExAC rs750238747, gnomAD rs750238747, REVEL 0.60, CADD 33.00
- G51E (p.Gly51Glu), gnomAD 3-89127272-G-A, REVEL 0.56, CADD 32.00
- G51G (p.Gly51Gly), rs2106974664, gnomAD 3-89127273-G-A, CADD 24.00
- W52* (p.Trp52Ter), NCI-TCGA Cosmic COSV6071, NCI-TCGA Cosmic COSV6072, cosmic curated COSV60725, Variant assessed as somatic; high impact.
- E53K (p.Glu53Lys), NCI-TCGA Cosmic COSV6069, cosmic curated COSV60695, Variant assessed as somatic; moderate impact.
- E53D (p.Glu53Asp), gnomAD 3-89209865-A-C, REVEL 0.25, CADD 23.60
Public EPHA3 analysis runs
- EPHA3 analysis run — EPHA3 (2,675 variants) — completed 2026-09-01