Is EDA p.Thr338= (c.1014G>A) pathogenic?

EDA p.Thr338= (c.1014G>A) is classified Benign in EDA (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-17). Ultra-rare (popmax 0.0477%, sas); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Thr338= (c.1014G>A)?

EDA p.Thr338= (c.1014G>A) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Thr338= (c.1014G>A) in the general population?

EDA p.Thr338= (c.1014G>A) is ultra-rare (popmax 0.0477%, sas) (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.Thr338=

c.1014G>A · rs750674219 · VCV710891

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0477%, sas)

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 -4.6	GERP -9.4
Overall
CADD	0.435	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0477% South Asian · 27/56,598 alleles

Filtering AF 0.0336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.00331% 40/1,207,869 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0477%	2,096
African / African-American	0.0053%	18,856
East Asian	0.00297%	33,668
Remaining individualsnot grpmax-eligible	0.0021%	47,575
European (non-Finnish)	0.000894%	111,839

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.Thr338=
Coding: c.1014G>A
MANE Select: NM_001399
dbSNP: rs750674219
Type: single nucleotide variant
Location: chrX:70035447 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 338: a β-strand; a disulfide bond; the thd domain; a UniProt-annotated variant site (in sthagx1 and xhed; likely pathogenic; decreased function in positive regulation of canonical nf-kappab signal transduction)

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.Thr338Met Pathogenic ★★ ⚠ same residue
EDA p.Thr338Ala Likely 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

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-thr338 (accessed [today's date]).

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