Is NSD1 p.Pro1217Ser (c.3649C>T) pathogenic?

NSD1 p.Pro1217Ser (c.3649C>T) is classified Conflicting classifications of pathogenicity in NSD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.0653); Ultra-rare (popmax 0.0147%, afr); Associated with Sotos syndrome.

What condition is associated with NSD1 p.Pro1217Ser (c.3649C>T)?

NSD1 p.Pro1217Ser (c.3649C>T) is associated with Sotos syndrome (ClinVar).

How common is NSD1 p.Pro1217Ser (c.3649C>T) in the general population?

NSD1 p.Pro1217Ser (c.3649C>T) is ultra-rare (popmax 0.0147%, afr) (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.Pro1217Ser (c.3649C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

NSD1 p.Pro1217Ser

c.3649C>T · rs372004424 · VCV352884

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sotos syndrome

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -2.9, phastCons 0.94
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.47 · regional, not allelic
Overall
CADD	3.754	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 0.0147% African / African-American · 11/75,010 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00105% 17/1,614,060 alleles · ultra-rare exomes 8/1,461,892 · genomes 9/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,819
Remaining individualsnot grpmax-eligible	0.0096%	10,418

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.Pro1217Ser
Coding: c.3649C>T
MANE Select: NM_022455
dbSNP: rs372004424
Type: single nucleotide variant
Location: chr5:177212048 (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.Pro1217Thr 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-pro1217ser (accessed [today's date]).

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