Is PMS2 p.Ile18Val (c.52A>G) pathogenic?

PMS2 p.Ile18Val (c.52A>G) is classified Likely benign in PMS2 (ClinVar, Expert panel, 40 submitters; last evaluated 2014-10-10). AlphaMissense: likely benign (0.2899); Low-frequency (popmax 1.22%, nfe); Associated with Lynch syndrome 1.

What condition is associated with PMS2 p.Ile18Val (c.52A>G)?

PMS2 p.Ile18Val (c.52A>G) is associated with Lynch syndrome 1, endometrial carcinoma, Lynch syndrome (ClinVar).

How common is PMS2 p.Ile18Val (c.52A>G) in the general population?

PMS2 p.Ile18Val (c.52A>G) is low-frequency (popmax 1.22%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PMS2 p.Ile18Val (c.52A>G)?

AlphaMissense predicts likely benign (score 0.2899) — an in-silico prediction, not a clinical call.

PMS2 p.Ile18Val

c.52A>G · rs63750123 · VCV41713

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 40 submitters

AlphaMissense

likely benign

0.2899 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2899	likely benign
REVEL	0.636	indeterminate
SaProt	LLR -11.45	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	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

Grpmax group 1.22% European (non-Finnish) · 14,342/1,179,692 alleles

Filtering AF 1.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 1.1% 17,667/1,610,660 alleles · low-frequency exomes 16,400/1,458,362 · genomes 1,267/152,298 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.21%	31
European (non-Finnish)grpmax	1.22%	82
Remaining individualsnot grpmax-eligible	1.06%	95
South Asian	0.367%	272
Admixed American	0.288%	347
African / African-American	0.172%	581
Middle Eastern	0.0903%	1,107
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,959

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile18Val
Coding: c.52A>G
MANE Select: NM_000535
dbSNP: rs63750123
Type: single nucleotide variant
Location: chr7:6006003 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 18: a UniProt-annotated variant site (in lynch4; uncertain significance); a UniProt-annotated variant site (in lynch4; likely benign; normal dna mismatch repair activity)

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

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Ile18= Benign/Likely benign ★★ same residue
PMS2 p.Ile18Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ile18fs Pathogenic ★★ same residue
PMS2 p.Ile18Phe 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-ile18val (accessed [today's date]).

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