Is MSH6 p.Ile172Val (c.514A>G) pathogenic?

MSH6 p.Ile172Val (c.514A>G) is classified Uncertain significance in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.1547); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Ile172Val (c.514A>G)?

MSH6 p.Ile172Val (c.514A>G) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH6 p.Ile172Val (c.514A>G) in the general population?

MSH6 p.Ile172Val (c.514A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Ile172Val (c.514A>G)?

AlphaMissense predicts likely benign (score 0.1547) — an in-silico prediction, not a clinical call.

MSH6 p.Ile172Val

c.514A>G · rs2530518008 · VCV2708419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1547	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH6
Protein: p.Ile172Val
Coding: c.514A>G
MANE Select: NM_000179
dbSNP: rs2530518008
Type: single nucleotide variant
Location: chr2:47795950 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 172: an α-helix

Full MSH6 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

Similar variants

MSH6 p.Ile172Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Ile172Lys Uncertain significance ★ ⚠ same residue
MSH6 p.Ile172Met Uncertain significance ★ ⚠ same residue
MSH6 c.3173-3C>G Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3557-1G>A Likely pathogenic ★★ same condition
MSH6 c.3557-1G>C Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3557-1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3646+1G>A Pathogenic/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/msh6-p-ile172val (accessed [today's date]).

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