Is PMS2 p.Val309Phe (c.925G>T) pathogenic?

PMS2 p.Val309Phe (c.925G>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-04). AlphaMissense: ambiguous (0.4592); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Val309Phe (c.925G>T)?

PMS2 p.Val309Phe (c.925G>T) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Val309Phe (c.925G>T) in the general population?

PMS2 p.Val309Phe (c.925G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PMS2 p.Val309Phe (c.925G>T)?

AlphaMissense predicts ambiguous (score 0.4592) — an in-silico prediction, not a clinical call.

PMS2 p.Val309Phe

c.925G>T · rs763718441 · VCV1320827

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4592	ambiguous
REVEL	0.716	pathogenic-leaning
SaProt	LLR -14.60	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.97
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	23.6	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 0.00167% Admixed American · 1/59,958 alleles

Overall 0.000125% 2/1,594,858 alleles · very rare exomes 2/1,442,622 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,958
South Asian	0.0011%	90,696

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: PMS2
Protein: p.Val309Phe
Coding: c.925G>T
MANE Select: NM_000535
dbSNP: rs763718441
Type: single nucleotide variant
Location: chr7:5992036 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 309: an α-helix

Full PMS2 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: Lynch syndrome 4

Similar variants

PMS2 p.Val309Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Val309Ile Uncertain significance ★ ⚠ same residue
PMS2 p.Val309= Likely benign ★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+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/pms2-p-val309phe (accessed [today's date]).

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