Is PMS2 p.Asp782= (c.2346C>T) pathogenic?

PMS2 p.Asp782= (c.2346C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.033%, mid); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Asp782= (c.2346C>T)?

PMS2 p.Asp782= (c.2346C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Asp782= (c.2346C>T) in the general population?

PMS2 p.Asp782= (c.2346C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

PMS2 p.Asp782=

c.2346C>T · rs139031103 · VCV378882

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.397	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.98
Overall
CADD	8.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00131% 21/1,606,160 alleles · ultra-rare exomes 19/1,455,822 · genomes 2/150,338 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.00804%	12,440
Admixed American	0.00502%	19,931
East Asian	0.00449%	22,278
African / African-American	0.00404%	24,725
South Asian	0.00331%	30,205
European (non-Finnish)	0.000255%	391,629

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.Asp782=
Coding: c.2346C>T
MANE Select: NM_000535
dbSNP: rs139031103
Type: single nucleotide variant
Location: chr7:5977687 (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

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Asp782Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp782Asn Uncertain significance ★ ⚠ same residue
PMS2 p.Asp782Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.Asp782Val Uncertain significance ★ ⚠ same residue
PMS2 p.Asp782del Uncertain significance ★★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G 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-asp782 (accessed [today's date]).

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