Is PMS2 p.Cys27Phe (c.80G>T) pathogenic?

PMS2 p.Cys27Phe (c.80G>T) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). AlphaMissense: likely pathogenic (0.84); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Cys27Phe (c.80G>T)?

PMS2 p.Cys27Phe (c.80G>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Cys27Phe (c.80G>T) in the general population?

PMS2 p.Cys27Phe (c.80G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Cys27Phe (c.80G>T)?

AlphaMissense predicts likely pathogenic (score 0.84) — an in-silico prediction, not a clinical call.

PMS2 p.Cys27Phe

c.80G>T · rs2128845886 · VCV1482631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.84 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.84	likely pathogenic
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Cys27Phe
Coding: c.80G>T
MANE Select: NM_000535
dbSNP: rs2128845886
Type: single nucleotide variant
Location: chr7:6005975 (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 nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PMS2 p.Cys27Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys27Ter Pathogenic ★ same residue
PMS2 p.Cys27Trp Uncertain significance ★ ⚠ same residue
PMS2 p.Cys27= Likely benign ★ same residue
PMS2 c.1145-2A>G Likely pathogenic ★★ same condition
PMS2 c.164-1G>A Pathogenic/Likely pathogenic ★★ same condition
PMS2 c.164-1G>C Pathogenic/Likely pathogenic ★★ same condition
PMS2 c.2006+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-cys27phe (accessed [today's date]).

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