Is EDA p.Leu253= (c.759A>G) pathogenic?

EDA p.Leu253= (c.759A>G) is classified Likely benign in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). Very rare (popmax 0.00439%, amr); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Leu253= (c.759A>G)?

EDA p.Leu253= (c.759A>G) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Leu253= (c.759A>G) in the general population?

EDA p.Leu253= (c.759A>G) is very rare (popmax 0.00439%, amr) (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.Leu253=

c.759A>G · rs757048479 · VCV1154706

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00439%, amr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -4.9, phastCons 0.72
Overall
CADD	6.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% Admixed American · 2/45,565 alleles

Filtering AF 0.000728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000483%

Overall 0.00108% 13/1,205,608 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00439%	22,783
European (non-Finnish)	0.00123%	81,146

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.Leu253=
Coding: c.759A>G
MANE Select: NM_001399
dbSNP: rs757048479
Type: single nucleotide variant
Location: chrX:70030486 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 253: a β-strand; the thd domain

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 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
EDA p.Ala349Thr 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-leu253 (accessed [today's date]).

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