Is MSH2 p.Asp283Val (c.848A>T) pathogenic?

MSH2 p.Asp283Val (c.848A>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.2396); Very rare (popmax 0.00225%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Asp283Val (c.848A>T) in the general population?

MSH2 p.Asp283Val (c.848A>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about MSH2 p.Asp283Val (c.848A>T)?

AlphaMissense predicts likely benign (score 0.2396) — an in-silico prediction, not a clinical call.

MSH2 p.Asp283Val

Q: What condition is associated with MSH2 p.Asp283Val (c.848A>T)?

MSH2 p.Asp283Val (c.848A>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.848A>T · rs770643326 · VCV455620

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.2396	likely benign
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -3.48	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	24.0	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 0.00225% East Asian · 1/44,522 alleles

Overall 6.21e-05% 1/1,609,920 alleles · very rare exomes 1/1,460,256 · genomes 0/149,664 · 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.Asp283Val
Coding: c.848A>T
MANE Select: NM_000251
dbSNP: rs770643326
Type: single nucleotide variant
Location: chr2:47414324 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 283: an α-helix; a UniProt-annotated variant site (in lynch1)

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.Asp283Gly Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp283= Benign/Likely benign ★★ same residue
MSH2 p.Asp283Tyr Likely benign ★★ ⚠ same residue
MSH2 p.Asp283Asn Uncertain significance ★ ⚠ same residue
MSH2 p.Asp283His Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>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/msh2-p-asp283val (accessed [today's date]).

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