Is PMS2 p.Asp784His (c.2350G>C) pathogenic?

PMS2 p.Asp784His (c.2350G>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-20). AlphaMissense: ambiguous (0.5343); Very rare (popmax 8.51e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Asp784His (c.2350G>C)?

PMS2 p.Asp784His (c.2350G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Asp784His (c.2350G>C) in the general population?

PMS2 p.Asp784His (c.2350G>C) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Asp784His (c.2350G>C)?

AlphaMissense predicts ambiguous (score 0.5343) — an in-silico prediction, not a clinical call.

PMS2 p.Asp784His

c.2350G>C · rs143340522 · VCV1790006

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5343 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5343	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -10.59	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,792 alleles

Overall 6.87e-05% 1/1,455,778 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.Asp784His
Coding: c.2350G>C
MANE Select: NM_000535
dbSNP: rs143340522
Type: single nucleotide variant
Location: chr7:5977683 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PMS2 p.Asp784= Benign/Likely benign ★★ same residue
PMS2 p.Asp784Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Asp784Gly Uncertain significance ★ ⚠ same residue
PMS2 p.Asp784delinsAlaGlnHis Uncertain significance ★ same residue
PMS2 p.Asp784Glu Uncertain significance ★ ⚠ same residue
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A 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-asp784his (accessed [today's date]).

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