NSD1 (Q96L73) variants and mutations
NSD1 (also known as Q96L73) is a human protein-coding gene encoding a histone-lysine N-methyltransferase, H3 lysine-36 specific protein. It regulates developmental transcription through chromatin modification, including H3K36 methylation. Haploinsufficiency causes Sotos syndrome with childhood overgrowth, characteristic facial features, and developmental delay, while somatic rearrangements occur in some leukemias. This analysis covers 4,996 NSD1 variants and mutations. Of these, 51% have computational variant effect predictions. Disease context includes Sotos syndrome, Beckwith-Wiedemann syndrome, and acute myeloid leukemia. Example NSD1 variants include D2E, D2D, and Q3H.
Variant analysis overview
- Gene: NSD1
- Protein: Q96L73
- UniProt accession: Q96L73
- Organism: Homo sapiens
- Variants analyzed: 4996
- Variant scope: all variants
- Completed: 2026-08-22
Variant and mutation evidence
- Variant composition: 4,653 unspecified-consequence records; 151 synonymous variants; 150 missense variants; 20 frameshift variants; 12 stop-gained variants; 4 in-frame insertions; 6 in-frame deletions
- Prediction scores: 2,557 variants have prediction scores (51% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Sotos syndrome, Beckwith-Wiedemann syndrome, acute myeloid leukemia, hereditary disease, head and neck squamous cell carcinoma, Weaver syndrome, neurodegenerative disease, neurodevelopmental disorder, Intellectual disability, Neurodevelopmental delay, squamous cell lung carcinoma, type 2 diabetes mellitus.
Protein structure and variant hotspots
- Protein features: 5 domains; 5 binding sites; 8 post-translational modification sites.
- Structural context: 506 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, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable NSD1 variants
Examples include D2E, D2D, Q3H, Q3E, T4N, T4S, C5R, C5Y. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- D2E (p.Asp2Glu), ExAC rs774217599, gnomAD rs774217599, REVEL 0.34, CADD 23.60
- D2D (p.Asp2Asp), gnomAD 5-177135109-T-C, CADD 13.70
- Q3H (p.Gln3His), Ensembl rs2149755159
- Q3E (p.Gln3Glu), gnomAD 5-177135110-C-G, REVEL 0.27, CADD 20.50
- T4N (p.Thr4Asn), ExAC rs745589817, TOPMed rs745589817, gnomAD rs745589817, REVEL 0.29, CADD 22.90
- T4S (p.Thr4Ser), gnomAD rs1756202193, REVEL 0.29, CADD 22.40, Likely benign, not provided
- C5R (p.Cys5Arg), Ensembl rs2149755170
- C5Y (p.Cys5Tyr), gnomAD rs1169930104, REVEL 0.67, CADD 23.60
- E6K (p.Glu6Lys), gnomAD 5-177135119-G-A, REVEL 0.47, CADD 23.90
- L7I (p.Leu7Ile), rs368345846, ClinGen CA3576832, ClinVar RCV003232443, ClinVar RCV004809684, REVEL 0.39, CADD 18.30, Conflicting interpretations, Sotos syndrome; not provided
- L7P (p.Leu7Pro), TOPMed rs995047182, gnomAD rs995047182, REVEL 0.49, CADD 25.90, Conflicting interpretations, not provided; Sotos syndrome; Inborn genetic diseases
- L7L (p.Leu7Leu), gnomAD 5-177135124-A-G, CADD 9.30
- P8S (p.Pro8Ser), rs760160996, ClinGen CA132833964, ClinVar RCV003276166, Ensembl rs760160996, REVEL 0.22, CADD 8.25, Likely benign, Inborn genetic diseases
- P8L (p.Pro8Leu), gnomAD 5-177135126-C-T, REVEL 0.33, CADD 21.30
- P8P (p.Pro8Pro), gnomAD 5-177135127-C-T, CADD 11.40
- R9* (p.Arg9Ter), TOPMed rs1397807209, CADD 35.00
- R9I (p.Arg9Ile), rs1756203781, ClinGen CA362290026, ClinVar RCV003232581, ClinVar RCV006470437, REVEL 0.60, CADD 29.70, Conflicting interpretations, not provided; Sotos syndrome
- R9K (p.Arg9Lys), NCI-TCGA Cosmic COSV6177, Variant assessed as somatic; moderate impact.
- R9G (p.Arg9Gly), gnomAD 5-177135128-A-G, REVEL 0.43, CADD 23.20
- R10I (p.Arg10Ile), NCI-TCGA Cosmic COSV6177, Ensembl rs1581089074, REVEL 0.62, CADD 25.40, Uncertain significance
- R10K (p.Arg10Lys), rs1581089074, ClinGen CA362290038, ClinVar RCV005208726, Ensembl rs1581089074, REVEL 0.47, CADD 24.70, Uncertain significance, not provided
- R10R (p.Arg10Arg), rs776826212, gnomAD 5-177135133-A-G, CADD 13.80
- R10G (p.Arg10Gly), rs1353809467, gnomAD 5-177136873-A-G, CADD 4.27
- R10S (p.Arg10Ser), rs1453984892, gnomAD 5-177136875-A-C, CADD 1.62
- R10C (p.Arg10Cys), rs544005934, gnomAD 5-177136903-C-T, CADD 4.51
- R10L (p.Arg10Leu), gnomAD 5-177136904-G-T, CADD 0.58
- R10H (p.Arg10His), rs376850081, gnomAD 5-177136904-G-A, CADD 0.76
- R10W (p.Arg10Trp), rs1443028884, gnomAD 5-177136906-C-T, CADD 2.02
- R10Q (p.Arg10Gln), rs142168402, gnomAD 5-177136907-G-A, CADD 2.63
- N11H (p.Asn11His), TOPMed rs1449658273, gnomAD rs1449658273, REVEL 0.43, CADD 25.20
- N11Y (p.Asn11Tyr), gnomAD 5-177135134-A-T, REVEL 0.53, CADD 26.10
- N11D (p.Asn11Asp), gnomAD 5-177135134-A-G, REVEL 0.34, CADD 25.40
- C12* (p.Cys12Ter), TOPMed rs1433725330, gnomAD rs1433725330
- C12R (p.Cys12Arg), rs143406017, ClinGen CA3576834, ClinVar RCV000419168, ClinVar RCV003231475, REVEL 0.71, CADD 24.40, Conflicting interpretations, not provided; not specified; Sotos syndrome
- C12W (p.Cys12Trp), TOPMed rs1433725330, gnomAD rs1433725330, REVEL 0.68, CADD 25.30
- C12C (p.Cys12Cys), gnomAD 5-177135139-T-C, CADD 13.40
- C12F (p.Cys12Phe), rs963580684, gnomAD 5-177136889-G-T, CADD 1.85
- L13M (p.Leu13Met), rs1348059308, ClinGen CA362290126, ClinVar RCV003208264, TOPMed rs1348059308, REVEL 0.37, CADD 22.80, Uncertain significance, Inborn genetic diseases
- L13C (p.Leu13Cys), rs1456928971, gnomAD 5-177135136-TTGTC, CADD 27.90
- L14L (p.Leu14Leu), rs765274455, gnomAD 5-177135143-C-T, CADD 12.90
- L14Q (p.Leu14Gln), gnomAD 5-177135144-T-A, REVEL 0.31, CADD 21.80
- P15L (p.Pro15Leu), Ensembl rs1562097474
- P15R (p.Pro15Arg), Ensembl rs1562097474
- P15S (p.Pro15Ser), ESP rs372331010, ExAC rs372331010, TOPMed rs372331010, gnomAD rs372331010, REVEL 0.22, CADD 15.40, Likely benign, not provided
- P15P (p.Pro15Pro), rs763541378, gnomAD 5-177135148-C-G, CADD 9.22
- F16L (p.Phe16Leu), Ensembl rs2149755256
- S17* (p.Ser17Ter), rs1756383012, gnomAD 5-177136886-C-G, CADD 1.79
- S17S (p.Ser17Ser), gnomAD 5-177136887-A-G, CADD 3.73
- N18S (p.Asn18Ser), 1000Genomes rs199661846, REVEL 0.28, CADD 23.00, Uncertain significance, Sotos syndrome; not provided
- P19L (p.Pro19Leu), rs1756207246, ClinGen CA362290260, NCI-TCGA Cosmic COSV6177, ClinVar RCV003232309, MutPred 0.35, Uncertain significance, Sotos syndrome
- P19T (p.Pro19Thr), ExAC rs766740770, gnomAD rs766740770, REVEL 0.23, CADD 22.60
- P19A (p.Pro19Ala), gnomAD 5-177135158-C-G, REVEL 0.19, CADD 21.90
- V20L (p.Val20Leu), rs377302741, ClinGen CA132834028, ClinVar RCV003232457, ClinVar RCV005095401, REVEL 0.35, CADD 22.30, Uncertain significance, Inborn genetic diseases; not provided; Sotos syndrome
- V20M (p.Val20Met), NCI-TCGA TCGA novel, ESP rs377302741, TOPMed rs377302741, REVEL 0.40, CADD 23.70, Uncertain significance
- L22L (p.Leu22Leu), gnomAD 5-177136884-G-A, CADD 0.84
- D23G (p.Asp23Gly), TOPMed rs1232406723, gnomAD rs1232406723, REVEL 0.52, CADD 25.30
- D23H (p.Asp23His), Ensembl rs2149755276
- D23N (p.Asp23Asn), Ensembl rs2149755276
- D23Y (p.Asp23Tyr), Ensembl rs2149755276
- A24V (p.Ala24Val), gnomAD rs1756207893, REVEL 0.45, CADD 22.30
- A24A (p.Ala24Ala), gnomAD 5-177135175-C-G, CADD 13.70
- A24S (p.Ala24Ser), gnomAD 5-177136918-G-T, CADD 2.69
- A24D (p.Ala24Asp), gnomAD 5-177136919-C-A, CADD 0.47
- P25A (p.Pro25Ala), ExAC rs766881071, TOPMed rs766881071, gnomAD rs766881071, REVEL 0.29, CADD 20.50
- P25H (p.Pro25His), ExAC rs767337519, gnomAD rs767337519, REVEL 0.34, CADD 24.70
- P25L (p.Pro25Leu), ExAC rs767337519, gnomAD rs767337519, REVEL 0.25, CADD 23.40
- P25R (p.Pro25Arg), ExAC rs767337519, gnomAD rs767337519
- P25S (p.Pro25Ser), ExAC rs766881071, TOPMed rs766881071, gnomAD rs766881071, REVEL 0.25, CADD 17.50, Likely benign, not provided
- P25T (p.Pro25Thr), ExAC rs766881071, TOPMed rs766881071, gnomAD rs766881071
- E26D (p.Glu26Asp), Ensembl rs2149755302
- E26G (p.Glu26Gly), rs752376308, ClinGen CA3576842, ClinVar RCV004493690, ClinVar RCV005104808, REVEL 0.39, CADD 23.90, Benign/Likely benign, Inborn genetic diseases; not provided
- E26K (p.Glu26Lys), gnomAD rs978430605, REVEL 0.38, CADD 28.60, Uncertain significance, not provided
- E26* (p.Glu26Ter), rs1258507155, gnomAD 5-177135173-G-GC, CADD 32.00
- K28K (p.Lys28Lys), gnomAD 5-177135187-G-A, CADD 12.70
- D29H (p.Asp29His), TOPMed rs1756209619, gnomAD rs1756209619
- D29N (p.Asp29Asn), TOPMed rs1756209619, gnomAD rs1756209619, REVEL 0.33, CADD 26.10
- D29G (p.Asp29Gly), gnomAD 5-177135189-A-G, REVEL 0.40, CADD 31.00
- D29V (p.Asp29Val), gnomAD 5-177135189-A-T, REVEL 0.48, CADD 32.00
- D29E (p.Asp29Glu), gnomAD 5-177135190-C-G, REVEL 0.41, CADD 17.80
- D29D (p.Asp29Asp), rs1460150422, gnomAD 5-177136911-C-T, CADD 2.87
- S30N (p.Ser30Asn), NCI-TCGA TCGA novel, Ensembl rs2149755309, Variant assessed as somatic; moderate impact.
- S30C (p.Ser30Cys), gnomAD 5-177136913-C-G, CADD 2.82
- S30F (p.Ser30Phe), rs922221697, gnomAD 5-177136913-C-T, CADD 3.38
- S30S (p.Ser30Ser), rs1369692658, gnomAD 5-177136914-C-T, CADD 2.04
- P31A (p.Pro31Ala), rs905320202, ClinGen CA132834070, ClinVar RCV001539286, TOPMed rs905320202, REVEL 0.37, CADD 22.60, Likely benign, not provided
- P31R (p.Pro31Arg), TOPMed rs1269686460, gnomAD rs1269686460, REVEL 0.47, CADD 24.50
- P31T (p.Pro31Thr), TOPMed rs905320202, gnomAD rs905320202, Likely benign
- P31S (p.Pro31Ser), gnomAD 5-177135194-C-T, REVEL 0.44, CADD 23.00
- F32S (p.Phe32Ser), rs1235429660, gnomAD 5-177135195-CT-C, CADD 23.60
- F32F (p.Phe32Phe), rs1474688900, gnomAD 5-177135199-C-T, CADD 15.70
- F32L (p.Phe32Leu), gnomAD 5-177135199-C-A, REVEL 0.45, CADD 25.60
- G33A (p.Gly33Ala), Ensembl rs1756210868
- G33D (p.Gly33Asp), Ensembl rs1756210868
- G33S (p.Gly33Ser), rs923849995, ClinGen CA132834073, ClinVar RCV005098503, Ensembl rs923849995, MutPred 0.06, Uncertain significance, not provided
- G33C (p.Gly33Cys), gnomAD 5-177136897-G-T, CADD 0.88
- G33G (p.Gly33Gly), rs1451422289, gnomAD 5-177136899-C-A, CADD 3.87
- N34Y (p.Asn34Tyr), Ensembl rs2149755330
- N34N (p.Asn34Asn), rs754317223, gnomAD 5-177135205-T-C, CADD 12.80
- G35A (p.Gly35Ala), Ensembl rs2149755339
- G35D (p.Gly35Asp), NCI-TCGA TCGA novel, REVEL 0.46, CADD 23.60, Variant assessed as somatic; moderate impact.
- G35S (p.Gly35Ser), rs777455412, NCI-TCGA Cosmic COSV6177, ExAC rs777455412, gnomAD rs777455412, REVEL 0.45, CADD 26.30, Variant assessed as somatic; moderate impact.
- Q36* (p.Gln36Ter), Ensembl rs2149755349
- Q36K (p.Gln36Lys), gnomAD 5-177135209-C-A, REVEL 0.26, CADD 22.50
- Q36Q (p.Gln36Gln), rs549091873, gnomAD 5-177135211-A-G, CADD 14.10
- S37* (p.Ser37Ter), rs562677696, gnomAD 5-177136925-C-A, CADD 0.41
- S37L (p.Ser37Leu), rs562677696, gnomAD 5-177136925-C-T, CADD 0.48
- S37S (p.Ser37Ser), rs910216751, gnomAD 5-177136926-G-A, CADD 0.82
- N38K (p.Asn38Lys), TOPMed rs1169250439, gnomAD rs1169250439, REVEL 0.23, CADD 22.90
- N38S (p.Asn38Ser), rs368524494, ClinGen CA3576845, ClinVar RCV005095350, ESP rs368524494, REVEL 0.25, CADD 15.90, Likely benign, not provided
- F39V (p.Phe39Val), Ensembl rs2149755370
- F39L (p.Phe39Leu), gnomAD 5-177135218-TTTTC, CADD 25.70
- E41E (p.Glu41Glu), rs1395825730, gnomAD 5-177135226-G-A, CADD 10.40
- E41* (p.Glu41Ter), rs944974487, gnomAD 5-177136945-G-T, CADD 4.51
- P42S (p.Pro42Ser), Ensembl rs1756212574
- L43R (p.Leu43Arg), Ensembl rs1756212980
- L43F (p.Leu43Phe), gnomAD 5-177135230-C-T, REVEL 0.29, CADD 18.50
- L39del (p.Leu39del), rs1756389054, gnomAD 5-177136927-ATCC-, CADD 2.08
- L43I (p.Leu43Ile), gnomAD 5-177136930-C-A, CADD 1.09
- L43H (p.Leu43His), rs1336034279, gnomAD 5-177136931-T-A, CADD 5.71
- L43L (p.Leu43Leu), rs1416811090, gnomAD 5-177136932-C-T, CADD 3.27
- N44H (p.Asn44His), TOPMed rs1319187083
- N44S (p.Asn44Ser), TOPMed rs1278011388, gnomAD rs1278011388, REVEL 0.39, CADD 23.00
- N44T (p.Asn44Thr), TOPMed rs1278011388, gnomAD rs1278011388, REVEL 0.37, CADD 23.30
- G45A (p.Gly45Ala), Ensembl rs2149755400
- G45V (p.Gly45Val), Ensembl rs2149755400
- G45W (p.Gly45Trp), Ensembl rs2149755394, REVEL 0.55, CADD 28.10
- G45R (p.Gly45Arg), gnomAD 5-177135236-G-A, REVEL 0.40, CADD 23.90
- C46R (p.Cys46Arg), Ensembl rs1581089514, REVEL 0.45, CADD 22.90
- C46S (p.Cys46Ser), Ensembl rs1581089514
- C46Y (p.Cys46Tyr), Ensembl rs2149755411, REVEL 0.40, CADD 23.10
- T47S (p.Thr47Ser), rs1562097679, ClinGen CA362290917, ClinVar RCV002314434, Ensembl rs1562097679, MutPred 0.14, Uncertain significance, Inborn genetic diseases
- T47A (p.Thr47Ala), gnomAD 5-177135242-A-G, REVEL 0.36, CADD 20.40
- M48V (p.Met48Val), rs200735877, ClinGen CA294796, ClinVar RCV003231169, ClinVar RCV004751291, REVEL 0.31, CADD 20.40, Conflicting interpretations, Sotos syndrome; not provided
- M48C (p.Met48Cys), gnomAD 5-177135243-CT-C, CADD 25.80
- M48L (p.Met48Leu), gnomAD 5-177135245-A-C, REVEL 0.37, CADD 21.60
- M48K (p.Met48Lys), gnomAD 5-177135246-T-A, REVEL 0.47, CADD 23.50
- M48I (p.Met48Ile), gnomAD 5-177135247-G-T, REVEL 0.29, CADD 19.80
- Q49* (p.Gln49Ter), rs1336273625, ClinGen CA362290956, ClinVar RCV003232202, ClinVar RCV003236864, CADD 35.00, Uncertain significance
- Q49E (p.Gln49Glu), gnomAD rs1336273625, REVEL 0.25, CADD 18.60, Uncertain significance
- Q49L (p.Gln49Leu), gnomAD rs1338887740
- Q49Q (p.Gln49Gln), gnomAD 5-177136953-G-A, CADD 9.46
- L50L (p.Leu50Leu), rs1581089582, gnomAD 5-177135253-A-G, CADD 10.20
- S51L (p.Ser51Leu), gnomAD rs1756215957, REVEL 0.25, CADD 23.70
- S51P (p.Ser51Pro), rs778646937, ClinGen CA3576846, ClinVar RCV005058954, ExAC rs778646937, REVEL 0.31, CADD 13.30, Likely benign, not provided
- S51W (p.Ser51Trp), gnomAD rs1756215957, REVEL 0.38, CADD 25.60
- S51T (p.Ser51Thr), gnomAD 5-177135254-T-A, REVEL 0.30, CADD 18.90
- S51S (p.Ser51Ser), rs727504052, gnomAD 5-177135256-G-T, CADD 11.80
- T52I (p.Thr52Ile), Ensembl rs2149755440
- V53D (p.Val53Asp), Ensembl rs2149755457
- V53I (p.Val53Ile), ExAC rs776883958, gnomAD rs776883958
- V53L (p.Val53Leu), ExAC rs776883958, gnomAD rs776883958, REVEL 0.28, CADD 21.00
- S54N (p.Ser54Asn), ExAC rs748405383, gnomAD rs748405383, REVEL 0.35, CADD 23.00
- S54R (p.Ser54Arg), gnomAD rs1216715825, REVEL 0.45, CADD 25.60
- S54T (p.Ser54Thr), ExAC rs748405383, gnomAD rs748405383, REVEL 0.36, CADD 17.40
- S54G (p.Ser54Gly), gnomAD 5-177135263-A-G, REVEL 0.40, CADD 23.60
- G55A (p.Gly55Ala), Ensembl rs2149755470
- T56I (p.Thr56Ile), ExAC rs773358220, gnomAD rs773358220, REVEL 0.34, CADD 23.00
- T56P (p.Thr56Pro), ExAC rs769958493, gnomAD rs769958493, REVEL 0.38, CADD 23.00
- S57C (p.Ser57Cys), Ensembl rs2149755480
- S57F (p.Ser57Phe), Ensembl rs2149755480
- S57T (p.Ser57Thr), TOPMed rs1298442193, gnomAD rs1298442193, REVEL 0.22, CADD 17.10
- Q58E (p.Gln58Glu), ExAC rs762876721, gnomAD rs762876721, REVEL 0.29, CADD 22.30
- Q58K (p.Gln58Lys), ExAC rs762876721, gnomAD rs762876721
- Q58R (p.Gln58Arg), rs2480086482, ClinGen CA362291301, ClinVar RCV003443999, Uncertain significance, not provided
- Q58* (p.Gln58Ter), gnomAD 5-177135275-C-T, CADD 35.00
- N59T (p.Asn59Thr), Ensembl rs2149755497
- N59Y (p.Asn59Tyr), Ensembl rs2149755491
- N59M (p.Asn59Met), gnomAD 5-177135275-CA-C, CADD 25.30
- A60D (p.Ala60Asp), Ensembl rs1756218400, Uncertain significance
- A60P (p.Ala60Pro), Ensembl rs2149755502
- A60V (p.Ala60Val), Ensembl rs1756218400, REVEL 0.34, CADD 22.80, Uncertain significance, not provided; Sotos syndrome
- A60G (p.Ala60Gly), gnomAD 5-177135282-C-G, REVEL 0.31, CADD 19.70
- A60A (p.Ala60Ala), rs772907473, gnomAD 5-177135283-T-A, CADD 14.10
- Y61H (p.Tyr61His), TOPMed rs1364964092, gnomAD rs1364964092, REVEL 0.45, CADD 23.80
- Y61C (p.Tyr61Cys), gnomAD 5-177135285-A-G, REVEL 0.59, CADD 26.30
- Y61Y (p.Tyr61Tyr), rs1756219106, gnomAD 5-177135286-T-C, CADD 11.10
- G62G (p.Gly62Gly), gnomAD 5-177135289-A-G, CADD 14.10
- Q63R (p.Gln63Arg), Ensembl rs1756219351, REVEL 0.48, CADD 24.80, Uncertain significance, not provided
- Q63E (p.Gln63Glu), gnomAD 5-177135290-C-G, REVEL 0.38, CADD 22.90
- Q63Q (p.Gln63Gln), rs2149755530, gnomAD 5-177135292-A-G, CADD 11.40
Public NSD1 analysis runs
- NSD1 analysis run — NSD1 (4,996 variants) — completed 2026-08-22