Is PMS2 p.Ile787Phe (c.2359A>T) pathogenic?

PMS2 p.Ile787Phe (c.2359A>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.7515); Ultra-rare (popmax 0.0134%, amr); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Ile787Phe (c.2359A>T)?

PMS2 p.Ile787Phe (c.2359A>T) is associated with Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ile787Phe (c.2359A>T) in the general population?

PMS2 p.Ile787Phe (c.2359A>T) is ultra-rare (popmax 0.0134%, 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.Ile787Phe (c.2359A>T)?

AlphaMissense predicts likely pathogenic (score 0.7515) — an in-silico prediction, not a clinical call.

PMS2 p.Ile787Phe

c.2359A>T · rs191300933 · VCV233208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7515 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.7515	likely pathogenic
REVEL	0.712	pathogenic-leaning
SaProt	LLR -11.93	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 4.4	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	23.5	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

Grpmax group 0.0134% Admixed American · 8/59,776 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00484%

Overall 0.000498% 8/1,605,950 alleles · ultra-rare exomes 6/1,455,744 · genomes 2/150,206 · joint denominator

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.Ile787Phe
Coding: c.2359A>T
MANE Select: NM_000535
dbSNP: rs191300933
Type: single nucleotide variant
Location: chr7:5977674 (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 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.Ile787Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile787Met Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile787Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile787Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile787= Likely benign ★ 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

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-ile787phe (accessed [today's date]).

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