Is ESPN p.Glu752fs (c.2254_2275del) pathogenic?

ESPN p.Glu752fs (c.22542275del) is classified Pathogenic in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-08). Ultra-rare (popmax 0.0175%, afr); Associated with ESPN-related disorder.

What condition is associated with ESPN p.Glu752fs (c.2254_2275del)?

ESPN p.Glu752fs (c.2254_2275del) is associated with ESPN-related disorder (ClinVar).

How common is ESPN p.Glu752fs (c.2254_2275del) in the general population?

ESPN p.Glu752fs (c.2254_2275del) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

ESPN p.Glu752fs

c.2254_2275del · VCV4934024

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Conditions

ESPN-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
NMD	predicted	premature termination codon in exon 10 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -14	GERP -3.1
Overall
CADD	36.0	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 0.0175% African / African-American · 13/74,396 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00818%

Overall 0.000817% 13/1,591,640 alleles · ultra-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: ESPN
Protein: p.Glu752fs
Coding: c.2254_2275del
MANE Select: NM_031475
Type: Deletion
Location: chr1:6452025 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76

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

Disease context

ESPN-related disorder

Similar variants

ESPN p.Glu752= Likely benign ★★ same residue
ESPN p.Gln713fs Likely pathogenic ★ same condition
ESPN p.Glu608fs Likely pathogenic ★ same condition
ESPN p.Leu176fs Likely pathogenic ★ same condition
ESPN p.Glu752Gln Uncertain significance ★ ⚠ same residue
ESPN p.Glu752Lys Uncertain significance ★ ⚠ same residue
ESPN p.Leu783fs Conflicting classifications of pathogenicity ★ same condition
ESPN c.1464+1G>T 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/espn-p-glu752fs (accessed [today's date]).

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