Is MSH3 p.Pro147Ser (c.439C>T) pathogenic?

MSH3 p.Pro147Ser (c.439C>T) is classified Conflicting classifications of pathogenicity in MSH3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0819); Ultra-rare (popmax 0.0223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro147Ser (c.439C>T)?

MSH3 p.Pro147Ser (c.439C>T) is associated with hereditary neoplastic syndrome, endometrial carcinoma, familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Pro147Ser (c.439C>T) in the general population?

MSH3 p.Pro147Ser (c.439C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about MSH3 p.Pro147Ser (c.439C>T)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

MSH3 p.Pro147Ser

c.439C>T · rs977366961 · VCV662540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -5.28	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 4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	15.97	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 0.0223% East Asian · 10/44,886 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000929% 15/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
African / African-American	0.00267%	37,469
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	8.47e-05%	1,179,993

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.Pro147Ser
Coding: c.439C>T
MANE Select: NM_002439
dbSNP: rs977366961
Type: single nucleotide variant
Location: chr5:80665223 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 147: the 'interaction with exo1' region

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

Also linked: endometrial carcinoma familial adenomatous polyposis 4

Similar variants

MSH3 p.Pro147Ala Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro147His Uncertain significance ★ ⚠ same residue
MSH3 p.Pro147Leu Uncertain significance ★ ⚠ same residue
MSH3 p.Pro147= Likely benign ★ same residue
MSH3 p.Pro147fs Pathogenic ★★ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>A 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/msh3-p-pro147ser (accessed [today's date]).

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