Is PMS2 p.Asp249fs (c.746_753del) pathogenic?

PMS2 p.Asp249fs (c.746753del) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-05). Very rare (popmax 0.00223%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Asp249fs (c.746_753del)?

PMS2 p.Asp249fs (c.746_753del) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Asp249fs (c.746_753del) in the general population?

PMS2 p.Asp249fs (c.746_753del) is very rare (popmax 0.00223%, eas) (gnomAD).

PMS2 p.Asp249fs

c.746_753del · rs587782710 · VCV142778

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,812 alleles

Overall 6.87e-05% 1/1,456,526 alleles · very rare

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.Asp249fs
Coding: c.746_753del
MANE Select: NM_000535
dbSNP: rs587782710
Type: Deletion
Location: chr7:5997376 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 249: 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.Asp249= Benign/Likely benign ★★ same residue
PMS2 p.Asp249Glu Uncertain significance ★ ⚠ same residue
PMS2 p.Asp249Gly Uncertain significance ★ ⚠ same residue
PMS2 p.Asp249His Uncertain significance ★ ⚠ same residue
PMS2 p.Asp249Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.Asp249Val Uncertain significance ★ ⚠ same residue
PMS2 c.989-296_1144+706del Pathogenic ★★★ same condition
PMS2 p.Glu180_Tyr181insTer 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-asp249fs (accessed [today's date]).

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