Is EDA p.Thr378Met (c.1133C>T) pathogenic?

EDA p.Thr378Met (c.1133C>T) is classified Pathogenic in EDA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-13). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1; Associated with EDA-related disorder.

What condition is associated with EDA p.Thr378Met (c.1133C>T)?

EDA p.Thr378Met (c.1133C>T) is associated with EDA-related disorder, X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Thr378Met (c.1133C>T) in the general population?

EDA p.Thr378Met (c.1133C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDA p.Thr378Met (c.1133C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

EDA p.Thr378Met

c.1133C>T · rs1569407346 · VCV583138

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EDA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic ✓ concordant with ClinVar · top 8% in EDA
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -11.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 4.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	31.0	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.Thr378Met
Coding: c.1133C>T
MANE Select: NM_001399
dbSNP: rs1569407346
Type: single nucleotide variant
Location: chrX:70035566 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 378: a UniProt-annotated variant site (in xhed); a β-strand; the thd domain

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

Similar variants

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
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-thr378met (accessed [today's date]).

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