Is PMS2 p.Ser248fs (c.741_742insGTGTGTGAAG) pathogenic?

PMS2 p.Ser248fs (c.741742insGTGTGTGAAG) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-11). Very rare (popmax 0.00843%, nfe); Associated with PMS2-related disorder.

What condition is associated with PMS2 p.Ser248fs (c.741_742insGTGTGTGAAG)?

PMS2 p.Ser248fs (c.741_742insGTGTGTGAAG) is associated with PMS2-related disorder, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ser248fs (c.741_742insGTGTGTGAAG) in the general population?

PMS2 p.Ser248fs (c.741_742insGTGTGTGAAG) is very rare (popmax 0.00843%, nfe) (gnomAD).

PMS2 p.Ser248fs

c.741_742insGTGTGTGAAG · rs756653193 · VCV1328224

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00843%, nfe)

Conditions

PMS2-related disorder

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 4.2	phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00843% European (non-Finnish) · 99/1,173,792 alleles

Filtering AF 0.00706% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00655%

Overall 0.00637% 102/1,601,618 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00843%	11,856
African / African-American	0.00275%	36,316
Remaining individualsnot grpmax-eligible	0.00161%	62,148

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.Ser248fs
Coding: c.741_742insGTGTGTGAAG
MANE Select: NM_000535
dbSNP: rs756653193
Type: Insertion
Location: chr7:5997387 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 248: an α-helix

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PMS2-related disorder

Also linked: hereditary neoplastic syndrome

Similar variants

PMS2 p.Ser248Ter Likely pathogenic ★ same residue
PMS2 p.Ser248Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser248= Benign/Likely benign ★★ same residue
PMS2 p.Ser248Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Ser248delinsValTer Pathogenic ★ same residue
PMS2 p.Asp55delinsAsnTer Pathogenic/Likely pathogenic ★★ same condition
PMS2 p.Gly497fs Pathogenic/Likely pathogenic ★★ same condition
PMS2 p.Gly72fs Pathogenic/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-ser248fs (accessed [today's date]).

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