Is PMS2 p.Leu42= (c.126A>G) pathogenic?

PMS2 p.Leu42= (c.126A>G) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-19). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Leu42= (c.126A>G)?

PMS2 p.Leu42= (c.126A>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Leu42= (c.126A>G) in the general population?

PMS2 p.Leu42= (c.126A>G) is absent from gnomAD v4.1 (gnomAD).

PMS2 p.Leu42=

c.126A>G · VCV3421542

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 1.8	phastCons 0.99
Overall
CADD	11.03	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.Leu42=
Coding: c.126A>G
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:6005929 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 42: a UniProt-annotated variant site (in lynch4; strongly decreased dna mismatch repair activity in an in vitro assay; loss of atpase activity; reduced protein stability compared to wild-type; loss of structural identity); an α-helix

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

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Leu42Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Leu42Ter Pathogenic ★ same residue
PMS2 p.Leu42Ser Uncertain significance ★ ⚠ same residue
PMS2 p.Leu42_Glu44del Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Leu42fs Pathogenic ★ 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

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-leu42 (accessed [today's date]).

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