Is EDA p.Arg153His (c.458G>A) pathogenic?

EDA p.Arg153His (c.458G>A) is classified Conflicting classifications of pathogenicity in EDA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0628); Low-frequency (popmax 1.48%, sas); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Arg153His (c.458G>A)?

EDA p.Arg153His (c.458G>A) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Arg153His (c.458G>A) in the general population?

EDA p.Arg153His (c.458G>A) is low-frequency (popmax 1.48%, sas) (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.Arg153His (c.458G>A)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

EDA p.Arg153His

c.458G>A · rs140642493 · VCV702172

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.48%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -2.4
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	6.199	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 1.48% South Asian · 843/56,806 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.37%

Overall 0.222% 2,689/1,210,273 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.48%	67
Middle Eastern	0.965%	104
Ashkenazi Jewishnot grpmax-eligible	0.858%	117
Remaining individualsnot grpmax-eligible	0.296%	338
European (non-Finnish)	0.158%	631
Amishnot grpmax-eligible	0.146%	687
Finnishnot grpmax-eligible	0.0386%	2,591
Admixed American	0.0349%	2,868
East Asian	0.0267%	3,747
African / African-American	0.0209%	4,785

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.Arg153His
Coding: c.458G>A
MANE Select: NM_001399
dbSNP: rs140642493
Type: single nucleotide variant
Location: chrX:69957088 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 153: a UniProt-annotated variant site (in xhed; abolishes proteolytic processing); a UniProt-annotated variant site (in xhed; likely benign); the 'disordered' region

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.Arg153Cys Pathogenic ★★ ⚠ same residue
EDA p.Arg153= Likely 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

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-arg153his (accessed [today's date]).

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