Is MSH2 p.Asn331Asp (c.991A>G) pathogenic?

MSH2 p.Asn331Asp (c.991A>G) is classified Uncertain significance in MSH2 (ClinVar, Expert panel, 12 submitters; last evaluated 2018-06-13). AlphaMissense: likely benign (0.3028); Very rare (popmax 0.00289%, nfe); Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Asn331Asp (c.991A>G)?

MSH2 p.Asn331Asp (c.991A>G) is associated with Lynch syndrome 1, Lynch syndrome, Muir-Torre syndrome (ClinVar).

How common is MSH2 p.Asn331Asp (c.991A>G) in the general population?

MSH2 p.Asn331Asp (c.991A>G) is very rare (popmax 0.00289%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about MSH2 p.Asn331Asp (c.991A>G)?

AlphaMissense predicts likely benign (score 0.3028) — an in-silico prediction, not a clinical call.

MSH2 p.Asn331Asp

c.991A>G · rs267607938 · VCV91271

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.3028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3028	likely benign
REVEL	0.757	pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.86, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	21.2	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 0.00289% European (non-Finnish) · 34/1,177,998 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0023% 37/1,611,828 alleles · very rare exomes 33/1,459,592 · genomes 4/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00289%	34,647
African / African-American	0.00267%	37,449
Remaining individualsnot grpmax-eligible	0.0016%	62,428

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.Asn331Asp
Coding: c.991A>G
MANE Select: NM_000251
dbSNP: rs267607938
Type: single nucleotide variant
Location: chr2:47416344 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 331: a UniProt-annotated variant site (in lynch1; uncertain significance; no effect on msh2 splicing)

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

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Muir-Torre syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 2

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Asn331Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asn331= Benign ★ same residue
MSH2 p.Asn331fs Pathogenic ★ same residue
MSH2 p.Asn331_Cys333delinsSer Uncertain significance ★ same residue
MSH2 p.Asn331His Uncertain significance ★ ⚠ same residue
MSH2 p.Asn331Tyr Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T 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/msh2-p-asn331asp (accessed [today's date]).

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