Is PMS2 p.Val738Phe (c.2212G>T) pathogenic?

PMS2 p.Val738Phe (c.2212G>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.3187); Rare (popmax 0.302%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Val738Phe (c.2212G>T)?

PMS2 p.Val738Phe (c.2212G>T) is associated with hereditary neoplastic syndrome, Lynch syndrome 4, mismatch repair cancer syndrome 4 (ClinVar).

How common is PMS2 p.Val738Phe (c.2212G>T) in the general population?

PMS2 p.Val738Phe (c.2212G>T) is rare (popmax 0.302%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Val738Phe (c.2212G>T)?

AlphaMissense predicts likely benign (score 0.3187) — an in-silico prediction, not a clinical call.

PMS2 p.Val738Phe

c.2212G>T · rs758225108 · VCV548763

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.3187 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.302%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3187	likely benign
REVEL	0.474	indeterminate
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	1.688	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 0.302% South Asian · 273/90,506 alleles

Filtering AF 0.272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.261%

Overall 0.0175% 281/1,602,218 alleles · rare exomes 269/1,451,834 · genomes 12/150,384 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.302%	332
Remaining individualsnot grpmax-eligible	0.00968%	10,334
Admixed American	0.00167%	59,810
European (non-Finnish)	8.53e-05%	1,172,116

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.Val738Phe
Coding: c.2212G>T
MANE Select: NM_000535
dbSNP: rs758225108
Type: single nucleotide variant
Location: chr7:5978659 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

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 mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Val738Ala Uncertain significance ★★ same residue
PMS2 p.Val738Asp Uncertain significance ★ ⚠ same residue
PMS2 p.Val738Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Val738Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Val738fs Likely pathogenic ★ 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

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-val738phe (accessed [today's date]).

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