Is PMS2 p.Val321Ala (c.962T>C) pathogenic?

PMS2 p.Val321Ala (c.962T>C) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.316); Ultra-rare (popmax 0.029%, eas); Associated with mismatch repair cancer syndrome 4.

What condition is associated with PMS2 p.Val321Ala (c.962T>C)?

PMS2 p.Val321Ala (c.962T>C) is associated with mismatch repair cancer syndrome 4, Lynch syndrome, Lynch syndrome 1 (ClinVar).

How common is PMS2 p.Val321Ala (c.962T>C) in the general population?

PMS2 p.Val321Ala (c.962T>C) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about PMS2 p.Val321Ala (c.962T>C)?

AlphaMissense predicts likely benign (score 0.316) — an in-silico prediction, not a clinical call.

PMS2 p.Val321Ala

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.962T>C · rs186448384 · VCV219846

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.316 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mismatch repair cancer syndrome 4

Computational evidence

Protein change
AlphaMissense	0.316	likely benign
REVEL	0.719	pathogenic-leaning
SaProt	LLR -10.83	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	26.9	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 0.029% East Asian · 13/44,790 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000939% 15/1,597,510 alleles · ultra-rare exomes 12/1,445,206 · genomes 3/152,304 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,445
Remaining individualsnot grpmax-eligible	0.00161%	61,978
European (non-Finnish)	8.58e-05%	1,164,862

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.Val321Ala
Coding: c.962T>C
MANE Select: NM_000535
dbSNP: rs186448384
Type: single nucleotide variant
Location: chr7:5991999 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 321: a β-strand; a UniProt-annotated variant site (in lynch4; uncertain significance)

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

Disease context

mismatch repair cancer syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 1 ovarian cancer Lynch syndrome 4 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PMS2 p.Val321Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Val321Leu Uncertain significance ★ ⚠ 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
PMS2 c.251-2A>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-val321ala (accessed [today's date]).

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