Is PMS2 p.Ser229Pro (c.685T>C) pathogenic?

PMS2 p.Ser229Pro (c.685T>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.715); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ser229Pro (c.685T>C)?

PMS2 p.Ser229Pro (c.685T>C) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser229Pro (c.685T>C) in the general population?

PMS2 p.Ser229Pro (c.685T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Ser229Pro (c.685T>C)?

AlphaMissense predicts likely pathogenic (score 0.715) — an in-silico prediction, not a clinical call.

PMS2 p.Ser229Pro

c.685T>C · rs730881909 · VCV182799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.715 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.715	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -14.90	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	22.9	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.Ser229Pro
Coding: c.685T>C
MANE Select: NM_000535
dbSNP: rs730881909
Type: single nucleotide variant
Location: chr7:5999128 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 229: an α-helix

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

Also linked: Lynch syndrome Lynch syndrome 4

Similar variants

PMS2 p.Ser229Phe Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser229= Conflicting classifications of pathogenicity ★ same residue
PMS2 p.Ser229fs Pathogenic ★★ 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

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-ser229pro (accessed [today's date]).

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