Is MSH2 p.Ile192Phe (c.574A>T) pathogenic?

MSH2 p.Ile192Phe (c.574A>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-07). AlphaMissense: ambiguous (0.4778); Very rare (popmax 0.00333%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Ile192Phe (c.574A>T) in the general population?

MSH2 p.Ile192Phe (c.574A>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MSH2 p.Ile192Phe (c.574A>T)?

AlphaMissense predicts ambiguous (score 0.4778) — an in-silico prediction, not a clinical call.

MSH2 p.Ile192Phe

Q: What condition is associated with MSH2 p.Ile192Phe (c.574A>T)?

MSH2 p.Ile192Phe (c.574A>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.574A>T · rs768006988 · VCV455599

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.4778	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -10.28	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.67	acceptor gain · deltas
Pangolin	Δ0.60	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.3	GERP -1.2, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	26.8	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 0.00333% Admixed American · 2/60,014 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,142 alleles · very rare exomes 2/1,461,864 · genomes 0/152,278 · 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.Ile192Phe
Coding: c.574A>T
MANE Select: NM_000251
dbSNP: rs768006988
Type: single nucleotide variant
Location: chr2:47410301 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 192: 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: hereditary neoplastic syndrome

Similar variants

MSH2 p.Ile192= Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Ile192Leu Uncertain significance ★ ⚠ same residue
MSH2 p.Ile192Met Conflicting classifications of pathogenicity ★ ⚠ 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
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C 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-ile192phe (accessed [today's date]).

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