Is PMS2 p.Val415Met (c.1243G>A) pathogenic?

PMS2 p.Val415Met (c.1243G>A) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.093); Ultra-rare (popmax 0.035%, amr); Associated with hereditary nonpolyposis colon cancer.

What condition is associated with PMS2 p.Val415Met (c.1243G>A)?

PMS2 p.Val415Met (c.1243G>A) is associated with hereditary nonpolyposis colon cancer, endometrial carcinoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is PMS2 p.Val415Met (c.1243G>A) in the general population?

PMS2 p.Val415Met (c.1243G>A) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about PMS2 p.Val415Met (c.1243G>A)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

PMS2 p.Val415Met

c.1243G>A · rs138387687 · VCV142561

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary nonpolyposis colon cancer

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	phastCons 0.8
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	7.696	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 0.035% Admixed American · 21/59,992 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0165% 266/1,614,136 alleles · ultra-rare exomes 237/1,461,884 · genomes 29/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
European (non-Finnish)	0.0194%	5,153
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
African / African-American	0.004%	25,012
Finnishnot grpmax-eligible	0.00156%	64,026

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.Val415Met
Coding: c.1243G>A
MANE Select: NM_000535
dbSNP: rs138387687
Type: single nucleotide variant
Location: chr7:5987522 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 415: the 'disordered' region

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary nonpolyposis colon cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma hereditary breast ovarian cancer syndrome mismatch repair cancer syndrome 1 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Val415= Benign/Likely benign ★★ same residue
PMS2 p.Val415Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Val415Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Val415Gly 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
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-val415met (accessed [today's date]).

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