Is MSH3 p.Ser39Phe (c.116C>T) pathogenic?

MSH3 p.Ser39Phe (c.116C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0982); Very rare (popmax 6.23e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ser39Phe (c.116C>T)?

MSH3 p.Ser39Phe (c.116C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Ser39Phe (c.116C>T) in the general population?

MSH3 p.Ser39Phe (c.116C>T) is very rare (popmax 6.23e-05%) (gnomAD).

What do computational predictors say about MSH3 p.Ser39Phe (c.116C>T)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

MSH3 p.Ser39Phe

c.116C>T · rs2112797345 · VCV1476813

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.23e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.01	GERP -2.3
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	15.81	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 6.23e-05%

Overall 6.23e-05% 1/1,606,016 alleles · very rare exomes 1/1,454,172 · genomes 0/151,844 · 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: MSH3
Protein: p.Ser39Phe
Coding: c.116C>T
MANE Select: NM_002439
dbSNP: rs2112797345
Type: single nucleotide variant
Location: chr5:80654843 (GRCh38)

Full MSH3 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

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/msh3-p-ser39phe (accessed [today's date]).

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