Is MSH2 p.Asp49Val (c.146A>T) pathogenic?

MSH2 p.Asp49Val (c.146A>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-09-03). AlphaMissense: likely pathogenic (0.9826); Very rare (popmax 0.00112%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Asp49Val (c.146A>T) in the general population?

MSH2 p.Asp49Val (c.146A>T) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about MSH2 p.Asp49Val (c.146A>T)?

AlphaMissense predicts likely pathogenic (score 0.9826) — an in-silico prediction, not a clinical call.

MSH2 p.Asp49Val

Q: What condition is associated with MSH2 p.Asp49Val (c.146A>T)?

MSH2 p.Asp49Val (c.146A>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 1 (ClinVar).

c.146A>T · rs63750335 · VCV90675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.9826	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -16.05	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 8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	32.0	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 0.00112% South Asian · 1/89,542 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000622% 10/1,607,364 alleles · very rare exomes 10/1,455,020 · genomes 0/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00112%	89,542
European (non-Finnish)	0.000764%	130,933

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.Asp49Val
Coding: c.146A>T
MANE Select: NM_000251
dbSNP: rs63750335
Type: single nucleotide variant
Location: chr2:47403337 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 49: an α-helix

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: Lynch syndrome Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Asp49= Likely benign ★★ same residue
MSH2 p.Asp49Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp49Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp49Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp49fs Pathogenic ★★★ 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-asp49val (accessed [today's date]).

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