Is EDA p.Val365Ala (c.1094T>C) pathogenic?

EDA p.Val365Ala (c.1094T>C) is classified Pathogenic/Likely pathogenic in EDA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-04). AlphaMissense: likely pathogenic (0.8938); Very rare (popmax 0.00559%, nfe); Associated with EDA-related disorder.

What condition is associated with EDA p.Val365Ala (c.1094T>C)?

EDA p.Val365Ala (c.1094T>C) is associated with EDA-related disorder, tooth agenesis, X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Val365Ala (c.1094T>C) in the general population?

EDA p.Val365Ala (c.1094T>C) is very rare (popmax 0.00559%, nfe) (gnomAD).

What do computational predictors say about EDA p.Val365Ala (c.1094T>C)?

AlphaMissense predicts likely pathogenic (score 0.8938) — an in-silico prediction, not a clinical call.

EDA p.Val365Ala

c.1094T>C · rs397516654 · VCV44185

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.8938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00559%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EDA-related disorder

Computational evidence

Protein change
AlphaMissense	0.8938	likely pathogenic ✓ concordant with ClinVar
REVEL	0.666	pathogenic-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4.7, 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 0.00559% European (non-Finnish) · 50/894,124 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00431% 52/1,205,588 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00559%	17,882
Remaining individualsnot grpmax-eligible	0.0021%	47,516
African / African-American	0.00179%	55,815

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.Val365Ala
Coding: c.1094T>C
MANE Select: NM_001399
dbSNP: rs397516654
Type: single nucleotide variant
Location: chrX:70035527 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 365: the thd domain

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

Disease context

EDA-related disorder

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

Similar variants

EDA p.Val365Met Likely pathogenic ★★ ⚠ 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
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-val365ala (accessed [today's date]).

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