Is EDA p.Arg69Leu (c.206G>T) pathogenic?

EDA p.Arg69Leu (c.206G>T) is classified Conflicting classifications of pathogenicity in EDA (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2799); Rare (popmax 0.603%, nfe); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Arg69Leu (c.206G>T)?

EDA p.Arg69Leu (c.206G>T) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Arg69Leu (c.206G>T) in the general population?

EDA p.Arg69Leu (c.206G>T) is rare (popmax 0.603%, nfe) (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.Arg69Leu (c.206G>T)?

AlphaMissense predicts likely benign (score 0.2799) — an in-silico prediction, not a clinical call.

EDA p.Arg69Leu

c.206G>T · rs132630309 · VCV11032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.2799 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.603%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.2799	likely benign
REVEL	0.724	pathogenic-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8	GERP 0.58, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	23.2	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% European (non-Finnish) · 5,397/895,023 alleles

Filtering AF 0.589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.584%

Overall 0.485% 5,867/1,210,205 alleles · rare exomes 5,529/1,097,871 · genomes 338/112,334 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.603%	166
Remaining individualsnot grpmax-eligible	0.365%	274
Middle Eastern	0.276%	363
Ashkenazi Jewishnot grpmax-eligible	0.263%	380
South Asian	0.16%	624
Admixed American	0.106%	939
African / African-American	0.0818%	1,222
Finnishnot grpmax-eligible	0.0815%	1,227
East Asian	0.00297%	33,698

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.Arg69Leu
Coding: c.206G>T
MANE Select: NM_001399
dbSNP: rs132630309
Type: single nucleotide variant
Location: chrX:69616514 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 69: a UniProt-annotated variant site (in xhed)

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.Arg69Trp Benign ★ ⚠ 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
EDA p.Ala349Ser 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-arg69leu (accessed [today's date]).

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