Is MSH2 p.Asp319Tyr (c.955G>T) pathogenic?

MSH2 p.Asp319Tyr (c.955G>T) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: likely benign (0.212); Very rare (popmax 6.2e-05%); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Asp319Tyr (c.955G>T) in the general population?

MSH2 p.Asp319Tyr (c.955G>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about MSH2 p.Asp319Tyr (c.955G>T)?

AlphaMissense predicts likely benign (score 0.212) — an in-silico prediction, not a clinical call.

MSH2 p.Asp319Tyr

Q: What condition is associated with MSH2 p.Asp319Tyr (c.955G>T)?

MSH2 p.Asp319Tyr (c.955G>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.955G>T · rs876660605 · VCV408493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.212	likely benign
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	25.4	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 6.2e-05%

Overall 6.2e-05% 1/1,612,562 alleles · very rare exomes 1/1,460,244 · genomes 0/152,318 · joint denominator

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: MSH2
Protein: p.Asp319Tyr
Coding: c.955G>T
MANE Select: NM_000251
dbSNP: rs876660605
Type: single nucleotide variant
Location: chr2:47416308 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

MSH2 p.Asp319Asn Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp319Ala Uncertain significance ★ ⚠ same residue
MSH2 p.Asp319Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp319His Uncertain significance ★ ⚠ same residue
MSH2 p.Asp319Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp319= Likely benign ★ same residue
MSH2 p.Asp319fs Pathogenic ★ same residue
MSH2 c.1076+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/msh2-p-asp319tyr (accessed [today's date]).

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