Is PMS2 p.Cys331Ter (c.993C>A) pathogenic?

PMS2 p.Cys331Ter (c.993C>A) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-11). No allele count reported in gnomAD v4.1 (AN 1,580,872); Associated with mismatch repair cancer syndrome 4.

What condition is associated with PMS2 p.Cys331Ter (c.993C>A)?

PMS2 p.Cys331Ter (c.993C>A) is associated with mismatch repair cancer syndrome 4, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Cys331Ter (c.993C>A) in the general population?

PMS2 p.Cys331Ter (c.993C>A) is no allele count reported in gnomAD v4.1 (AN 1,580,872) (gnomAD).

PMS2 p.Cys331Ter

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.993C>A · rs186577215 · VCV1768663

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,580,872)

Conditions

mismatch repair cancer syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 10 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,580,872). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PMS2
Protein: p.Cys331Ter
Coding: c.993C>A
MANE Select: NM_000535
dbSNP: rs186577215
Type: single nucleotide variant
Location: chr7:5989951 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 331: an α-helix

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 4 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PMS2 p.Cys331Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys331Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys331= Conflicting classifications of pathogenicity ★ same residue
PMS2 p.Cys331Arg 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

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-cys331ter (accessed [today's date]).

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