Is NSD1 p.Arg1663His (c.4988G>A) pathogenic?

NSD1 p.Arg1663His (c.4988G>A) is classified Uncertain significance in NSD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-09). AlphaMissense: likely pathogenic (0.9236); Absent from gnomAD v4.1; Associated with Sotos syndrome.

What condition is associated with NSD1 p.Arg1663His (c.4988G>A)?

NSD1 p.Arg1663His (c.4988G>A) is associated with Sotos syndrome (ClinVar).

How common is NSD1 p.Arg1663His (c.4988G>A) in the general population?

NSD1 p.Arg1663His (c.4988G>A) is absent from gnomAD v4.1 (gnomAD).

How is Sotos syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NSD1 p.Arg1663His (c.4988G>A)?

AlphaMissense predicts likely pathogenic (score 0.9236) — an in-silico prediction, not a clinical call.

NSD1 p.Arg1663His

c.4988G>A · rs1562269357 · VCV574136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9236 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sotos syndrome

Computational evidence

Protein change
AlphaMissense	0.9236	likely pathogenic
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -10.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 11 kb · p 4.2e-16 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NSD1
Protein: p.Arg1663His
Coding: c.4988G>A
MANE Select: NM_022455
dbSNP: rs1562269357
Type: single nucleotide variant
Location: chr5:177260010 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 45.26 · 4 PDB

Full NSD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sotos syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sotos syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

NSD1 p.Arg1663Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
NSD1 c.1064-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.3921+1G>A Likely pathogenic ★★ same condition
NSD1 c.4192+2T>G Pathogenic ★★ same condition
NSD1 c.4378+1G>A Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4766-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4966+1G>A Pathogenic ★★ same condition
NSD1 c.4966+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nsd1-p-arg1663his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown