Is PMS2 p.Leu239Val (c.715C>G) pathogenic?

PMS2 p.Leu239Val (c.715C>G) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-30). AlphaMissense: likely benign (0.1295); No allele count reported in gnomAD v4.1 (AN 1,564,346); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Leu239Val (c.715C>G)?

PMS2 p.Leu239Val (c.715C>G) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is PMS2 p.Leu239Val (c.715C>G) in the general population?

PMS2 p.Leu239Val (c.715C>G) is no allele count reported in gnomAD v4.1 (AN 1,564,346) (gnomAD).

What do computational predictors say about PMS2 p.Leu239Val (c.715C>G)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

PMS2 p.Leu239Val

c.715C>G · rs1554301543 · VCV1038131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,564,346)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	24.8	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

No allele count reported in gnomAD v4.1 (AN 1,564,346). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PMS2
Protein: p.Leu239Val
Coding: c.715C>G
MANE Select: NM_000535
dbSNP: rs1554301543
Type: single nucleotide variant
Location: chr7:5997414 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 239: a β-strand

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.Leu239Arg Uncertain significance ★★ ⚠ same residue
PMS2 p.Leu239Phe Uncertain significance ★★ ⚠ same residue
PMS2 p.Leu239= Likely benign ★ same residue
PMS2 p.Leu239His 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

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-leu239val (accessed [today's date]).

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