Is PMS2 p.Leu684Pro (c.2051T>C) pathogenic?

PMS2 p.Leu684Pro (c.2051T>C) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-04). AlphaMissense: likely pathogenic (0.9964); Very rare (popmax 8.62e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Leu684Pro (c.2051T>C)?

PMS2 p.Leu684Pro (c.2051T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Leu684Pro (c.2051T>C) in the general population?

PMS2 p.Leu684Pro (c.2051T>C) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Leu684Pro (c.2051T>C)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

PMS2 p.Leu684Pro

c.2051T>C · VCV4140472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic · top 1% in PMS2
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -14.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	29.7	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

Grpmax group 8.62e-05% European (non-Finnish) · 1/1,160,420 alleles

Overall 6.31e-05% 1/1,584,302 alleles · very rare exomes 1/1,432,514 · genomes 0/151,788 · 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.Leu684Pro
Coding: c.2051T>C
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:5982947 (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.Leu684Gln Uncertain significance ★ ⚠ same residue
PMS2 p.Leu684Met Uncertain significance ★ same residue
PMS2 p.Leu684Val Uncertain significance ★ ⚠ same residue
PMS2 p.Leu684= Likely benign ★ 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
PMS2 c.2174+1G>A 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-leu684pro (accessed [today's date]).

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