Is PMS2 p.Ile193Phe (c.577A>T) pathogenic?

PMS2 p.Ile193Phe (c.577A>T) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-19). AlphaMissense: likely pathogenic (0.6016); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ile193Phe (c.577A>T)?

PMS2 p.Ile193Phe (c.577A>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Ile193Phe (c.577A>T) in the general population?

PMS2 p.Ile193Phe (c.577A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Ile193Phe (c.577A>T)?

AlphaMissense predicts likely pathogenic (score 0.6016) — an in-silico prediction, not a clinical call.

PMS2 p.Ile193Phe

c.577A>T · rs1784819145 · VCV1046828

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6016 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.6016	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -11.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.42	acceptor loss · deltas
Pangolin	Δ0.45	loss · gain 0.43 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.15	phastCons 0.046
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 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

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.Ile193Phe
Coding: c.577A>T
MANE Select: NM_000535
dbSNP: rs1784819145
Type: single nucleotide variant
Location: chr7:5999236 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 193: an α-helix

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.Ile193Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile193= 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
PMS2 c.2006+1G>A Likely pathogenic ★★ same condition
PMS2 c.2007-2A>C Pathogenic ★★ same condition
PMS2 c.2007-2A>G 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-ile193phe (accessed [today's date]).

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