Is PMS2 p.Phe267Cys (c.800T>G) pathogenic?

PMS2 p.Phe267Cys (c.800T>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4435); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with PMS2 p.Phe267Cys (c.800T>G)?

PMS2 p.Phe267Cys (c.800T>G) is associated with Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Phe267Cys (c.800T>G) in the general population?

PMS2 p.Phe267Cys (c.800T>G) is absent from gnomAD v4.1 (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.Phe267Cys (c.800T>G)?

AlphaMissense predicts ambiguous (score 0.4435) — an in-silico prediction, not a clinical call.

PMS2 p.Phe267Cys

c.800T>G · rs1034075819 · VCV2855760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4435 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.4435	ambiguous
REVEL	0.72	pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	27.7	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.Phe267Cys
Coding: c.800T>G
MANE Select: NM_000535
dbSNP: rs1034075819
Type: single nucleotide variant
Location: chr7:5997329 (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

Lynch syndrome — 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.Phe267= Benign/Likely benign ★★ same residue
PMS2 p.Phe267Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Phe267fs Pathogenic ★ same residue
PMS2 p.Phe267Ter 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

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-phe267cys (accessed [today's date]).

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