Is PMS2 p.Val243Phe (c.727G>T) pathogenic?

PMS2 p.Val243Phe (c.727G>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1171); Ultra-rare (popmax 0.0233%, sas); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Val243Phe (c.727G>T)?

PMS2 p.Val243Phe (c.727G>T) is associated with Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Val243Phe (c.727G>T) in the general population?

PMS2 p.Val243Phe (c.727G>T) is ultra-rare (popmax 0.0233%, sas) (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.Val243Phe (c.727G>T)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

PMS2 p.Val243Phe

c.727G>T · rs867655834 · VCV419274

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.59
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0233% South Asian · 20/85,862 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0101% 153/1,517,224 alleles · ultra-rare exomes 127/1,395,922 · genomes 26/121,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0233%	4,293
African / African-American	0.019%	5,274
Admixed American	0.0171%	5,846
East Asian	0.0161%	6,222
Ashkenazi Jewishnot grpmax-eligible	0.014%	7,130
Remaining individualsnot grpmax-eligible	0.01%	9,954
European (non-Finnish)	0.00823%	12,149
Finnishnot grpmax-eligible	0.00506%	19,754

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.Val243Phe
Coding: c.727G>T
MANE Select: NM_000535
dbSNP: rs867655834
Type: single nucleotide variant
Location: chr7:5997402 (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.Val243Leu 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
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.251-2A>G Likely pathogenic ★★★ same condition
PMS2 c.705+1G>T 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-val243phe (accessed [today's date]).

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