Is EDA p.Ala259fs (c.776del) pathogenic?

EDA p.Ala259fs (c.776del) is classified Likely pathogenic in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). Associated with EDA-related disorder.

What condition is associated with EDA p.Ala259fs (c.776del)?

EDA p.Ala259fs (c.776del) is associated with EDA-related disorder (ClinVar).

EDA p.Ala259fs

c.776del · VCV4951271

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

EDA-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 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 4.8, phastCons 1

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

Variant & gene context

Gene: EDA
Protein: p.Ala259fs
Coding: c.776del
MANE Select: NM_001399
Type: Deletion
Location: chrX:70030503 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 259: a β-strand; the thd domain; a UniProt-annotated variant site (in sthagx1; decreased interaction with edar for isoform 1; decreased interaction with eda2r for isoform 3; changed downstream signaling)

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

Disease context

EDA-related disorder

Similar variants

EDA p.217_219PGP[1] Pathogenic ★★ same condition
EDA p.Asn185_Pro196del Pathogenic ★★ same condition
EDA p.Gly85fs Pathogenic ★★ same condition
EDA p.Asn185fs Likely pathogenic ★ same condition
EDA p.Ile336fs Likely pathogenic ★ same condition
EDA p.Pro31fs Likely pathogenic ★ same condition
EDA p.Ala259= Likely benign ★ same residue
EDA p.Ala259Glu Pathogenic ⚠ same residue

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/eda-p-ala259fs (accessed [today's date]).

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