Is PMS2 p.Pro296Ser (c.886C>T) pathogenic?

PMS2 p.Pro296Ser (c.886C>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.9771); Ultra-rare (popmax 0.0133%, amr); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Pro296Ser (c.886C>T)?

PMS2 p.Pro296Ser (c.886C>T) is associated with Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Pro296Ser (c.886C>T) in the general population?

PMS2 p.Pro296Ser (c.886C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about PMS2 p.Pro296Ser (c.886C>T)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

PMS2 p.Pro296Ser

c.886C>T · rs375553553 · VCV411034

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic · top 8% in PMS2
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -13.54	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 12	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	29.9	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

Grpmax group 0.0133% Admixed American · 8/59,990 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00062% 10/1,613,394 alleles · ultra-rare exomes 10/1,461,120 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	8.48e-05%	1,179,362

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PMS2
Protein: p.Pro296Ser
Coding: c.886C>T
MANE Select: NM_000535
dbSNP: rs375553553
Type: single nucleotide variant
Location: chr7:5995551 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 296: a β-strand

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

Disease context

Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Pro296Ala Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro296His Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro296= Benign/Likely benign ★★ same residue
PMS2 p.Pro296Leu 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-pro296ser (accessed [today's date]).

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