Is EDA p.Ala259= (c.777A>C) pathogenic?

EDA p.Ala259= (c.777A>C) is classified Likely benign in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). Very rare (popmax 0.000337%, nfe); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Ala259= (c.777A>C)?

EDA p.Ala259= (c.777A>C) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Ala259= (c.777A>C) in the general population?

EDA p.Ala259= (c.777A>C) is very rare (popmax 0.000337%, nfe) (gnomAD).

How is Hypohidrotic ectodermal dysplasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EDA p.Ala259=

c.777A>C · rs777145505 · VCV1101170

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000337%, nfe)

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -1.9, phastCons 1
Overall
CADD	8.781	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000337% European (non-Finnish) · 3/891,355 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000275% 3/1,091,152 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: EDA
Protein: p.Ala259=
Coding: c.777A>C
MANE Select: NM_001399
dbSNP: rs777145505
Type: single nucleotide variant
Location: chrX:70030504 (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

X-linked hypohidrotic ectodermal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypohidrotic ectodermal dysplasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

EDA p.Ala259Glu Pathogenic ⚠ same residue
EDA c.526+5G>T Likely pathogenic ★★ same condition
EDA c.527-2A>G Pathogenic/Likely pathogenic ★★ same condition
EDA c.706+1G>A Pathogenic/Likely pathogenic ★★ same condition
EDA c.707-13T>G Pathogenic ★★ same condition
EDA c.742-2A>G Pathogenic/Likely pathogenic ★★ same condition
EDA c.924+1G>T Likely pathogenic ★★ same condition
EDA p.Ala349Ser 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/eda-p-ala259 (accessed [today's date]).

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