Is PMS2 p.Asp782Val (c.2345A>T) pathogenic?

PMS2 p.Asp782Val (c.2345A>T) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-06). AlphaMissense: likely pathogenic (0.9676); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Asp782Val (c.2345A>T)?

PMS2 p.Asp782Val (c.2345A>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Asp782Val (c.2345A>T) in the general population?

PMS2 p.Asp782Val (c.2345A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PMS2 p.Asp782Val (c.2345A>T)?

AlphaMissense predicts likely pathogenic (score 0.9676) — an in-silico prediction, not a clinical call.

PMS2 p.Asp782Val

c.2345A>T · rs745500014 · VCV525829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9676 · 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	0.9676	likely pathogenic · top 10% in PMS2
REVEL	0.768	pathogenic-leaning
SaProt	LLR -14.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.1	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	33.0	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.Asp782Val
Coding: c.2345A>T
MANE Select: NM_000535
dbSNP: rs745500014
Type: single nucleotide variant
Location: chr7:5977688 (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.Asp782Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp782= Benign/Likely benign ★★ same residue
PMS2 p.Asp782del Uncertain significance ★★ same residue
PMS2 p.Asp782Asn Uncertain significance ★ ⚠ same residue
PMS2 p.Asp782Tyr 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-asp782val (accessed [today's date]).

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