Is EDA p.Glu164Ala (c.491A>C) pathogenic?

EDA p.Glu164Ala (c.491A>C) is classified Conflicting classifications of pathogenicity in EDA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-03). AlphaMissense: likely benign (0.1656); Rare (popmax 0.225%, eas); Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Glu164Ala (c.491A>C)?

EDA p.Glu164Ala (c.491A>C) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Glu164Ala (c.491A>C) in the general population?

EDA p.Glu164Ala (c.491A>C) is rare (popmax 0.225%, eas) (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.Glu164Ala (c.491A>C)?

AlphaMissense predicts likely benign (score 0.1656) — an in-silico prediction, not a clinical call.

EDA p.Glu164Ala

c.491A>C · rs397516663 · VCV44195

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1656 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.225%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.1656	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	23.3	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 0.225% East Asian · 76/33,710 alleles

Filtering AF 0.185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.00755% 91/1,205,355 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.225%	444
Remaining individualsnot grpmax-eligible	0.0295%	3,387
South Asian	0.00176%	56,683

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.Glu164Ala
Coding: c.491A>C
MANE Select: NM_001399
dbSNP: rs397516663
Type: single nucleotide variant
Location: chrX:69957121 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 164: 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 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
EDA p.Ala349Thr 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-glu164ala (accessed [today's date]).

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