Is MSH3 p.Pro6Ser (c.16C>T) pathogenic?

MSH3 p.Pro6Ser (c.16C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.0988); Ultra-rare (popmax 0.033%, nfe); Associated with familial adenomatous polyposis 4.

What condition is associated with MSH3 p.Pro6Ser (c.16C>T)?

MSH3 p.Pro6Ser (c.16C>T) is associated with familial adenomatous polyposis 4, endometrial carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro6Ser (c.16C>T) in the general population?

MSH3 p.Pro6Ser (c.16C>T) is ultra-rare (popmax 0.033%, nfe) (gnomAD).

How is MSH3-related polyposis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH3 p.Pro6Ser (c.16C>T)?

AlphaMissense predicts likely benign (score 0.0988) — an in-silico prediction, not a clinical call.

MSH3 p.Pro6Ser

c.16C>T · rs374904719 · VCV650237

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial adenomatous polyposis 4

Computational evidence

Protein change
AlphaMissense	0.0988	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.92	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 -0.83	GERP -1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	16.41	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

Grpmax group 0.033% European (non-Finnish) · 388/1,175,910 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.0252% 404/1,602,034 alleles · ultra-rare exomes 382/1,450,080 · genomes 22/151,954 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.00968%	10,331
African / African-American	0.00959%	10,433
Finnishnot grpmax-eligible	0.00479%	20,879

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.Pro6Ser
Coding: c.16C>T
MANE Select: NM_002439
dbSNP: rs374904719
Type: single nucleotide variant
Location: chr5:80654743 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB

Full MSH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial adenomatous polyposis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma hereditary neoplastic syndrome

For MSH3-related polyposis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

MSH3 p.Pro6Ala Uncertain significance ★★ ⚠ 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
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition
MSH3 c.1653+2T>A Likely pathogenic ★★ same condition
MSH3 c.1764-1G>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/msh3-p-pro6ser (accessed [today's date]).

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