Is PMS2 p.Ile122= (c.366T>C) pathogenic?

PMS2 p.Ile122= (c.366T>C) is classified Likely benign in PMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-21). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ile122= (c.366T>C)?

PMS2 p.Ile122= (c.366T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ile122= (c.366T>C) in the general population?

PMS2 p.Ile122= (c.366T>C) is absent from gnomAD v4.1 (gnomAD).

PMS2 p.Ile122=

c.366T>C · rs2128819275 · VCV1675018

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

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 1.4	phastCons 1
Overall
CADD	3.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Ile122=
Coding: c.366T>C
MANE Select: NM_000535
dbSNP: rs2128819275
Type: single nucleotide variant
Location: chr7:6002624 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 122: a β-strand

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.Ile122Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile122Val Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ile122Phe Uncertain significance ★ ⚠ 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
PMS2 c.705+1G>T 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-ile122 (accessed [today's date]).

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