Is MSH2 p.Ile192= (c.576C>T) pathogenic?

MSH2 p.Ile192= (c.576C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-11-17). Very rare (popmax 0.00534%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Ile192= (c.576C>T) in the general population?

MSH2 p.Ile192= (c.576C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

MSH2 p.Ile192=

Q: What condition is associated with MSH2 p.Ile192= (c.576C>T)?

MSH2 p.Ile192= (c.576C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 1 (ClinVar).

c.576C>T · rs864622381 · VCV220102

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -0.64, phastCons 1
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,896 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000558% 9/1,613,962 alleles · very rare exomes 4/1,461,864 · genomes 5/152,098 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,724
European (non-Finnish)	0.000424%	236,005

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.Ile192=
Coding: c.576C>T
MANE Select: NM_000251
dbSNP: rs864622381
Type: single nucleotide variant
Location: chr2:47410303 (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: Lynch syndrome Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ile192Leu Uncertain significance ★ ⚠ same residue
MSH2 p.Ile192Met Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ile192Phe 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-ile192 (accessed [today's date]).

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