Is PMS2 p.Ile240Phe (c.718A>T) pathogenic?

PMS2 p.Ile240Phe (c.718A>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-01). AlphaMissense: likely benign (0.1141); Very rare (popmax 0.000173%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ile240Phe (c.718A>T) in the general population?

PMS2 p.Ile240Phe (c.718A>T) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Ile240Phe (c.718A>T)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

PMS2 p.Ile240Phe

Q: What condition is associated with PMS2 p.Ile240Phe (c.718A>T)?

PMS2 p.Ile240Phe (c.718A>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.718A>T · rs746592049 · VCV650427

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.65	pathogenic-leaning
SaProt	LLR -10.01	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	phastCons 0.99
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	19.92	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 0.000173% European (non-Finnish) · 2/1,156,596 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000127% 2/1,573,456 alleles · very rare exomes 2/1,435,076 · genomes 0/138,380 · 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.Ile240Phe
Coding: c.718A>T
MANE Select: NM_000535
dbSNP: rs746592049
Type: single nucleotide variant
Location: chr7:5997411 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 240: a β-strand

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

PMS2 p.Ile240= Benign/Likely benign ★★ same residue
PMS2 p.Ile240Asn Uncertain significance ★ ⚠ same residue
PMS2 p.Ile240Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Ile240Met Uncertain significance ★ ⚠ same residue
PMS2 p.Ile240Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Ile240Val Uncertain significance ★ ⚠ same residue
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-ile240phe (accessed [today's date]).

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