Is PMS2 p.Asp60Ala (c.179A>C) pathogenic?

PMS2 p.Asp60Ala (c.179A>C) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.3441); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Asp60Ala (c.179A>C)?

PMS2 p.Asp60Ala (c.179A>C) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Asp60Ala (c.179A>C) in the general population?

PMS2 p.Asp60Ala (c.179A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Asp60Ala (c.179A>C)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

PMS2 p.Asp60Ala

c.179A>C · VCV3664599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.3441	ambiguous
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -7.51	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	27.9	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

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.Asp60Ala
Coding: c.179A>C
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:6004043 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 60: a UniProt-annotated variant site (normal dna mismatch repair activity); 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.Asp60Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60fs Pathogenic ★ same residue
PMS2 p.Asp60Glu Likely benign ★★★ 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-asp60ala (accessed [today's date]).

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