Is PMS2 p.Val501fs (c.1500del) pathogenic?

PMS2 p.Val501fs (c.1500del) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). Very rare (popmax 0.0011%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Val501fs (c.1500del)?

PMS2 p.Val501fs (c.1500del) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Val501fs (c.1500del) in the general population?

PMS2 p.Val501fs (c.1500del) is very rare (popmax 0.0011%, sas) (gnomAD).

PMS2 p.Val501fs

c.1500del · rs759151952 · VCV224541

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.02
Overall
CADD	2.062	PHRED · no single calibrated threshold — expert panels disagree
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

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 0.000186% 3/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,999
South Asiangrpmax	0.0011%	91,088

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val501fs
Coding: c.1500del
MANE Select: NM_000535
dbSNP: rs759151952
Type: Deletion
Location: chr7:5987265 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 501: the 'disordered' region

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 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Val501Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Val501Met Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Val501= Likely benign ★ same residue
PMS2 c.1145-1350_*20545del Pathogenic ★★★ same condition
PMS2 c.1145-?_2174+?del Pathogenic ★★★ same condition
PMS2 c.2276-113_2445+1596del Pathogenic ★★★ same condition
PMS2 c.2276-91_2445+790del Pathogenic ★★★ same condition
PMS2 c.24-?_163+?del 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-val501fs (accessed [today's date]).

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