Is PMS2 p.Cys276Phe (c.827G>T) pathogenic?

PMS2 p.Cys276Phe (c.827G>T) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-12). AlphaMissense: likely benign (0.2968); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Cys276Phe (c.827G>T)?

PMS2 p.Cys276Phe (c.827G>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Cys276Phe (c.827G>T) in the general population?

PMS2 p.Cys276Phe (c.827G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Cys276Phe (c.827G>T)?

AlphaMissense predicts likely benign (score 0.2968) — an in-silico prediction, not a clinical call.

PMS2 p.Cys276Phe

c.827G>T · VCV3632157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.2968	likely benign
REVEL	0.508	indeterminate
SaProt	LLR -11.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	22.8	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

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.Cys276Phe
Coding: c.827G>T
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:5995610 (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.Cys276Ter Pathogenic ★★ same residue
PMS2 p.Cys276Arg Uncertain significance ★★ same residue
PMS2 p.Cys276Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys276= Benign/Likely benign ★★ same residue
PMS2 p.Cys276Gly Uncertain significance ★ ⚠ same residue
PMS2 p.Cys276Ser Uncertain significance ★ ⚠ same residue
PMS2 p.Cys276Trp Uncertain significance ★ same residue
PMS2 c.1145-2A>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-cys276phe (accessed [today's date]).

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