Is PMS2 p.Ser270Pro (c.808T>C) pathogenic?

PMS2 p.Ser270Pro (c.808T>C) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: ambiguous (0.546); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ser270Pro (c.808T>C)?

PMS2 p.Ser270Pro (c.808T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ser270Pro (c.808T>C) in the general population?

PMS2 p.Ser270Pro (c.808T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Ser270Pro (c.808T>C)?

AlphaMissense predicts ambiguous (score 0.546) — an in-silico prediction, not a clinical call.

PMS2 p.Ser270Pro

c.808T>C · rs2536157086 · VCV1761949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.546 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.546	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -13.30	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	25.2	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.Ser270Pro
Coding: c.808T>C
MANE Select: NM_000535
dbSNP: rs2536157086
Type: single nucleotide variant
Location: chr7:5995629 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 270: a β-strand

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PMS2 p.Ser270Ter Pathogenic ★ same residue
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.705+1G>T Likely pathogenic ★★★ same condition
PMS2 c.989-2A>G Likely pathogenic ★★★ same condition
PMS2 p.Arg134Ter 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-ser270pro (accessed [today's date]).

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