Is EDA p.Arg289His (c.866G>A) pathogenic?

EDA p.Arg289His (c.866G>A) is classified Pathogenic/Likely pathogenic in EDA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.5359); Very rare (popmax 0.00123%, nfe); Associated with tooth agenesis.

What condition is associated with EDA p.Arg289His (c.866G>A)?

EDA p.Arg289His (c.866G>A) is associated with tooth agenesis, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1 (ClinVar).

How common is EDA p.Arg289His (c.866G>A) in the general population?

EDA p.Arg289His (c.866G>A) is very rare (popmax 0.00123%, nfe) (gnomAD).

What do computational predictors say about EDA p.Arg289His (c.866G>A)?

AlphaMissense predicts ambiguous (score 0.5359) — an in-silico prediction, not a clinical call.

EDA p.Arg289His

c.866G>A · rs876657641 · VCV228257

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5359 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

tooth agenesis

Computational evidence

Protein change
AlphaMissense	0.5359	ambiguous
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -5.78	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	28.0	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 0.00123% European (non-Finnish) · 11/895,362 alleles

Filtering AF 0.000659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.001% 11/1,098,037 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.Arg289His
Coding: c.866G>A
MANE Select: NM_001399
dbSNP: rs876657641
Type: single nucleotide variant
Location: chrX:70033470 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 289: a turn; 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); a UniProt-annotated variant site (in sthagx1); a UniProt-annotated variant site (in xhed; when associated in cis with c-290; loss of function in edar-mediated signaling when associated in cis with c-290; not secreted when associated in cis with c-290)

Full EDA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tooth agenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked hypohidrotic ectodermal dysplasia tooth agenesis, selective, X-linked, 1 ectodermal dysplasia syndrome

Similar variants

EDA p.Arg289Cys Pathogenic ★★ same residue
EDA p.Arg289Gly Uncertain significance ★ ⚠ same residue
EDA p.Arg289= Likely benign ★ same residue
EDA p.Arg289fs Pathogenic ★ same residue
EDA p.Arg289Gln 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

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-arg289his (accessed [today's date]).

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