Is NSD1 p.Arg1663Cys (c.4987C>T) pathogenic?

NSD1 p.Arg1663Cys (c.4987C>T) is classified Conflicting classifications of pathogenicity in NSD1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-05-21). AlphaMissense: likely pathogenic (0.9734); Very rare (popmax 0.00167%, amr); Associated with NSD1-related disorder.

What condition is associated with NSD1 p.Arg1663Cys (c.4987C>T)?

NSD1 p.Arg1663Cys (c.4987C>T) is associated with NSD1-related disorder, Sotos syndrome (ClinVar).

How common is NSD1 p.Arg1663Cys (c.4987C>T) in the general population?

NSD1 p.Arg1663Cys (c.4987C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about NSD1 p.Arg1663Cys (c.4987C>T)?

AlphaMissense predicts likely pathogenic (score 0.9734) — an in-silico prediction, not a clinical call.

NSD1 p.Arg1663Cys

c.4987C>T · rs587784134 · VCV159355

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NSD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9734	likely pathogenic
REVEL	0.983	strongly pathogenic-leaning
SaProt	LLR -10.84	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 7.7	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 0.000124% 2/1,614,014 alleles · very rare exomes 2/1,461,886 · genomes 0/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,180,026

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NSD1
Protein: p.Arg1663Cys
Coding: c.4987C>T
MANE Select: NM_022455
dbSNP: rs587784134
Type: single nucleotide variant
Location: chr5:177260009 (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

NSD1-related disorder

Also linked: Sotos syndrome

Similar variants

NSD1 p.Arg1663His Uncertain significance ★★ ⚠ 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.4303-1G>C Likely 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

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-arg1663cys (accessed [today's date]).

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