Is PMS2 p.Ile18= (c.54T>C) pathogenic?

PMS2 p.Ile18= (c.54T>C) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-28). Very rare (popmax 0.00017%, nfe); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Ile18= (c.54T>C)?

PMS2 p.Ile18= (c.54T>C) is associated with Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ile18= (c.54T>C) in the general population?

PMS2 p.Ile18= (c.54T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Ile18=

c.54T>C · rs878854054 · VCV237920

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Lynch syndrome 4

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 -5.8
Overall
CADD	1.778	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,798 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,778 alleles · very rare exomes 2/1,458,462 · genomes 0/152,316 · 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.Ile18=
Coding: c.54T>C
MANE Select: NM_000535
dbSNP: rs878854054
Type: single nucleotide variant
Location: chr7:6006001 (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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Ile18Val 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-ile18 (accessed [today's date]).

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