Is PMS2 p.Phe682= (c.2046T>C) pathogenic?

PMS2 p.Phe682= (c.2046T>C) is classified Likely benign in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). Very rare (popmax 0.000632%); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Phe682= (c.2046T>C)?

PMS2 p.Phe682= (c.2046T>C) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Phe682= (c.2046T>C) in the general population?

PMS2 p.Phe682= (c.2046T>C) is very rare (popmax 0.000632%) (gnomAD).

PMS2 p.Phe682=

c.2046T>C · VCV3667862

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000632%)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	phastCons 1
Overall
CADD	9.509	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000632%

Overall 0.000632% 10/1,581,712 alleles · very rare exomes 7/1,430,022 · genomes 3/151,690 · joint denominator

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.Phe682=
Coding: c.2046T>C
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:5982952 (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.Phe682Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe682Tyr 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-phe682 (accessed [today's date]).

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