Is PMS2 p.Val43del (c.125TAG[1]) pathogenic?

PMS2 p.Val43del (c.125TAG[1]) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-25). Very rare (popmax 0.0011%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Val43del (c.125TAG[1])?

PMS2 p.Val43del (c.125TAG[1]) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome, mismatch repair cancer syndrome 4 (ClinVar).

How common is PMS2 p.Val43del (c.125TAG[1]) in the general population?

PMS2 p.Val43del (c.125TAG[1]) is very rare (popmax 0.0011%, sas) (gnomAD).

PMS2 p.Val43del

c.125TAG[1] · rs1064794820 · VCV420961

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 · substitutions only
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,994 alleles

Overall 0.000124% 2/1,610,878 alleles · very rare exomes 2/1,458,550 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,994
European (non-Finnish)	8.48e-05%	1,179,852

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.Val43del
Coding: c.125TAG[1]
MANE Select: NM_000535
dbSNP: rs1064794820
Type: Microsatellite
Location: chr7:6005925 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 43: 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: hereditary neoplastic syndrome mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Val43Ile Uncertain significance ★★ ⚠ same residue
PMS2 p.Val43= Benign/Likely benign ★★ same residue
PMS2 p.Val43Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Val43Glu Uncertain significance ★ ⚠ same residue
PMS2 p.Val43Gly Uncertain significance ★ ⚠ same residue
PMS2 p.Val43Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Lys748fs Pathogenic ★★★ same condition
PMS2 p.Ala116fs 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-val43del (accessed [today's date]).

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