Is PMS2 p.Glu44fs (c.129del) pathogenic?

PMS2 p.Glu44fs (c.129del) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-30). Absent from gnomAD; Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Glu44fs (c.129del)?

PMS2 p.Glu44fs (c.129del) is associated with Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Glu44fs (c.129del) in the general population?

PMS2 p.Glu44fs (c.129del) is absent from gnomAD (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Glu44fs

c.129del · rs1060503148 · VCV411082

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Lynch syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PMS2
Protein: p.Glu44fs
Coding: c.129del
MANE Select: NM_000535
dbSNP: rs1060503148
Type: Deletion
Location: chr7:6005926 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 44: 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

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.Glu44_Asn45delinsAsp Uncertain significance ★ same residue
PMS2 p.Glu44Asp Uncertain significance ★★ ⚠ same residue
PMS2 p.Glu44Gln Uncertain significance ★★ ⚠ same residue
PMS2 p.Glu44Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Glu44Val Uncertain significance ★ ⚠ same residue
PMS2 c.989-296_1144+706del Pathogenic ★★★ same condition
PMS2 p.Glu180_Tyr181insTer Pathogenic ★★★ same condition
PMS2 p.Leu731fs 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-glu44fs (accessed [today's date]).

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