Is EDA p.Arg334Cys (c.1000C>T) pathogenic?

EDA p.Arg334Cys (c.1000C>T) is classified Benign in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.7264); Ultra-rare (popmax 0.0124%, afr); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Arg334Cys (c.1000C>T)?

EDA p.Arg334Cys (c.1000C>T) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Arg334Cys (c.1000C>T) in the general population?

EDA p.Arg334Cys (c.1000C>T) is ultra-rare (popmax 0.0124%, afr) (gnomAD).

How is Hypohidrotic ectodermal dysplasia inherited?

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

What do computational predictors say about EDA p.Arg334Cys (c.1000C>T)?

AlphaMissense predicts likely pathogenic (score 0.7264) — an in-silico prediction, not a clinical call.

EDA p.Arg334Cys

c.1000C>T · rs757610457 · VCV2720515

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.7264	likely pathogenic
REVEL	0.43	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 4.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% African / African-American · 7/56,562 alleles

Filtering AF 0.00573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00409%

Overall 0.00199% 24/1,207,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0124%	8,080
East Asian	0.0119%	8,426
European (non-Finnish)	0.00145%	68,803

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.Arg334Cys
Coding: c.1000C>T
MANE Select: NM_001399
dbSNP: rs757610457
Type: single nucleotide variant
Location: chrX:70035433 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 334: a β-strand; a disulfide bond; the thd domain; a UniProt-annotated variant site (in sthagx1; uncertain significance; decreased interaction with edar for isoform 1; decreased interaction with eda2r for isoform 3; changed downstream signaling; mildly 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.Arg334His Benign ★★ ⚠ same residue
EDA p.Arg334Pro Uncertain significance ★ ⚠ 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-arg334cys (accessed [today's date]).

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