Is ESPN p.Asp518fs (c.1552dup) pathogenic?

ESPN p.Asp518fs (c.1552dup) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-26). Very rare (popmax 8.82e-05%, nfe).

How common is ESPN p.Asp518fs (c.1552dup) in the general population?

ESPN p.Asp518fs (c.1552dup) is very rare (popmax 8.82e-05%, nfe) (gnomAD).

ESPN p.Asp518fs

c.1552dup · rs1193621448 · VCV2816843

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 8.82e-05%, nfe)

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 8 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.3	GERP 1.4, phastCons 1
Overall
CADD	35.0	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 8.82e-05% European (non-Finnish) · 1/1,133,324 alleles

Overall 0.000657% 1/152,102 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: ESPN
Protein: p.Asp518fs
Coding: c.1552dup
MANE Select: NM_031475
dbSNP: rs1193621448
Type: Duplication
Location: chr1:6448723 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 518: the 'disordered' region

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

Similar variants

ESPN p.His82fs Likely pathogenic ★ same type
ESPN p.Ser568fs Likely pathogenic ★ same type
ESPN p.Trp258Ter Likely pathogenic ★ same type
ESPN c.2053_2061+20dup Conflicting classifications of pathogenicity ★ same type
ESPN p.Pro567_Ser568insPro Uncertain significance ★ same type
ESPN c.295-147dup Likely benign ★ same type
ESPN c.489-236dup Benign ★ same type
ESPN c.676-57dup Benign ★ 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/espn-p-asp518fs (accessed [today's date]).

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