Is PMS2 p.Ile768Phe (c.2302A>T) pathogenic?

PMS2 p.Ile768Phe (c.2302A>T) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.3043); Very rare (popmax 8.51e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ile768Phe (c.2302A>T)?

PMS2 p.Ile768Phe (c.2302A>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Ile768Phe (c.2302A>T) in the general population?

PMS2 p.Ile768Phe (c.2302A>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Ile768Phe (c.2302A>T)?

AlphaMissense predicts likely benign (score 0.3043) — an in-silico prediction, not a clinical call.

PMS2 p.Ile768Phe

c.2302A>T · rs2128675445 · VCV1490140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.3043	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Pangolin	Δ0.49	gain · loss 0.42 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	24.3	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 8.51e-05% European (non-Finnish) · 1/1,174,864 alleles

Overall 6.87e-05% 1/1,455,680 alleles · very rare

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.Ile768Phe
Coding: c.2302A>T
MANE Select: NM_000535
dbSNP: rs2128675445
Type: single nucleotide variant
Location: chr7:5977731 (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

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

Similar variants

PMS2 p.Ile768Ser Uncertain significance ★★ same residue
PMS2 p.Ile768= Benign/Likely benign ★★ same residue
PMS2 p.Ile768Asn Uncertain significance ★ ⚠ same residue
PMS2 p.Ile768Met Uncertain significance ★ ⚠ same residue
PMS2 p.Ile768Thr Uncertain significance ★ ⚠ same residue
PMS2 c.1145-2A>G Likely pathogenic ★★ same condition
PMS2 c.164-1G>A Pathogenic/Likely pathogenic ★★ same condition
PMS2 c.164-1G>C Pathogenic/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-ile768phe (accessed [today's date]).

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