Is EDA p.Arg334His (c.1001G>A) pathogenic?

EDA p.Arg334His (c.1001G>A) is classified Benign in EDA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.8704); Rare (popmax 0.603%, eas); Associated with tooth agenesis, selective, X-linked, 1.

What condition is associated with EDA p.Arg334His (c.1001G>A)?

EDA p.Arg334His (c.1001G>A) is associated with tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Arg334His (c.1001G>A) in the general population?

EDA p.Arg334His (c.1001G>A) is rare (popmax 0.603%, eas) (gnomAD).

What do computational predictors say about EDA p.Arg334His (c.1001G>A)?

AlphaMissense predicts likely pathogenic (score 0.8704) — an in-silico prediction, not a clinical call.

EDA p.Arg334His

c.1001G>A · rs142948132 · VCV253055

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.8704 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.603%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tooth agenesis, selective, X-linked, 1

Computational evidence

Protein change
AlphaMissense	0.8704	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 4.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	26.4	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 0.603% East Asian · 203/33,678 alleles

Filtering AF 0.535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.509%

Overall 0.0382% 461/1,207,703 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.603%	166
Remaining individualsnot grpmax-eligible	0.118%	850
South Asian	0.0442%	2,262
Finnishnot grpmax-eligible	0.0259%	3,857
African / African-American	0.0212%	4,717
European (non-Finnish)	0.0169%	5,924
Admixed American	0.0044%	22,741

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.Arg334His
Coding: c.1001G>A
MANE Select: NM_001399
dbSNP: rs142948132
Type: single nucleotide variant
Location: chrX:70035434 (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

tooth agenesis, selective, X-linked, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked hypohidrotic ectodermal dysplasia

Similar variants

EDA p.Arg334Cys 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-arg334his (accessed [today's date]).

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