Is MSH6 p.Phe985Val (c.2953T>G) pathogenic?

MSH6 p.Phe985Val (c.2953T>G) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-27). AlphaMissense: likely benign (0.084); Very rare (popmax 0.00753%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Phe985Val (c.2953T>G)?

MSH6 p.Phe985Val (c.2953T>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Phe985Val (c.2953T>G) in the general population?

MSH6 p.Phe985Val (c.2953T>G) is very rare (popmax 0.00753%, amr) (gnomAD).

What do computational predictors say about MSH6 p.Phe985Val (c.2953T>G)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

MSH6 p.Phe985Val

c.2953T>G · rs1258152646 · VCV854321

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00753%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	20.4	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 0.00753% Admixed American · 4/53,154 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00148%

Overall 0.000254% 4/1,576,228 alleles · very rare exomes 2/1,424,110 · genomes 2/152,118 · 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: MSH6
Protein: p.Phe985Val
Coding: c.2953T>G
MANE Select: NM_000179
dbSNP: rs1258152646
Type: single nucleotide variant
Location: chr2:47800936 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 985: a turn

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH6 p.Phe985Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe985= Benign/Likely benign ★★ same residue
MSH6 p.Phe985Cys Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>G Likely pathogenic ★★★ same condition
MSH6 c.3647-1G>A 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-phe985val (accessed [today's date]).

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