Is MESP2 p.Val240fs (c.718dup) pathogenic?

MESP2 p.Val240fs (c.718dup) is classified Uncertain significance in MESP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). Very rare (popmax 0.0011%, sas).

How common is MESP2 p.Val240fs (c.718dup) in the general population?

MESP2 p.Val240fs (c.718dup) is very rare (popmax 0.0011%, sas) (gnomAD).

MESP2 p.Val240fs

c.718dup · rs756232049 · VCV1951168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 2
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP 0.96, phastCons 0.028

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,788 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,610,850 alleles · very rare exomes 4/1,458,604 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,394
South Asiangrpmax	0.0011%	90,788
European (non-Finnish)	0.00017%	589,630

Remaining individuals 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: MESP2
Protein: p.Val240fs
Coding: c.718dup
MANE Select: NM_001039958
dbSNP: rs756232049
Type: Duplication
Location: chr15:89777069 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 240: the 'disordered' region

Full MESP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MESP2 p.Asp29fs Pathogenic ★ same type
MESP2 p.Cys59fs Pathogenic ★ same type
MESP2 p.Gln188fs Likely pathogenic ★ same type
MESP2 p.Gln55fs Pathogenic ★ same type
MESP2 p.Glu65fs Pathogenic ★ same type
MESP2 p.Gly12fs Pathogenic ★ same type
MESP2 p.Ser142fs Likely pathogenic ★ same type
MESP2 p.Ser158fs Pathogenic ★ same type

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/mesp2-p-val240fs (accessed [today's date]).

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