Is PMS2 p.Val332Ile (c.994G>A) pathogenic?

PMS2 p.Val332Ile (c.994G>A) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.0919); Very rare (popmax 0.00336%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Val332Ile (c.994G>A)?

PMS2 p.Val332Ile (c.994G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Val332Ile (c.994G>A) in the general population?

PMS2 p.Val332Ile (c.994G>A) is very rare (popmax 0.00336%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Val332Ile (c.994G>A)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

PMS2 p.Val332Ile

c.994G>A · rs1236095389 · VCV455754

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	21.1	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 0.00336% South Asian · 3/89,362 alleles

Filtering AF 0.000892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000612%

Overall 0.00138% 22/1,596,500 alleles · very rare exomes 20/1,444,392 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00336%	29,787
Admixed American	0.00335%	29,859
East Asian	0.00224%	44,562
Remaining individualsnot grpmax-eligible	0.00162%	61,758
European (non-Finnish)	0.00129%	77,767

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.Val332Ile
Coding: c.994G>A
MANE Select: NM_000535
dbSNP: rs1236095389
Type: single nucleotide variant
Location: chr7:5989950 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 332: a β-strand

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Val332Asp Uncertain significance ★★ ⚠ same residue
PMS2 p.Val332Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Val332Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Val332= 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

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-val332ile (accessed [today's date]).

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