Is EDA p.Arg289Cys (c.865C>T) pathogenic?

EDA p.Arg289Cys (c.865C>T) is classified Pathogenic in EDA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.8794); Absent from gnomAD v4.1; Associated with EDA-related disorder.

What condition is associated with EDA p.Arg289Cys (c.865C>T)?

EDA p.Arg289Cys (c.865C>T) is associated with EDA-related disorder, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1 (ClinVar).

How common is EDA p.Arg289Cys (c.865C>T) in the general population?

EDA p.Arg289Cys (c.865C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDA p.Arg289Cys (c.865C>T)?

AlphaMissense predicts likely pathogenic (score 0.8794) — an in-silico prediction, not a clinical call.

EDA p.Arg289Cys

c.865C>T · rs879255551 · VCV253054

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8794 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EDA-related disorder

Computational evidence

Protein change
AlphaMissense	0.8794	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 4.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EDA
Protein: p.Arg289Cys
Coding: c.865C>T
MANE Select: NM_001399
dbSNP: rs879255551
Type: single nucleotide variant
Location: chrX:70033469 (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

EDA-related disorder

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

Similar variants

EDA p.Arg289His Pathogenic/Likely 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+2T>C Pathogenic/Likely pathogenic ★★ same condition
EDA c.526+5G>T Likely pathogenic ★★ same condition
EDA c.527-2A>G 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-arg289cys (accessed [today's date]).

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