Is EDAR p.Ala378Val (c.1133C>T) pathogenic?

EDAR p.Ala378Val (c.1133C>T) is classified Uncertain significance in EDAR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.9811); Absent from gnomAD v4.1; Associated with EDAR-related disorder.

What condition is associated with EDAR p.Ala378Val (c.1133C>T)?

EDAR p.Ala378Val (c.1133C>T) is associated with EDAR-related disorder, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (ClinVar).

How common is EDAR p.Ala378Val (c.1133C>T) in the general population?

EDAR p.Ala378Val (c.1133C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDAR p.Ala378Val (c.1133C>T)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

EDAR p.Ala378Val

c.1133C>T · rs2105371700 · VCV1702963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EDAR-related disorder

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic · top 9% in EDAR
REVEL	0.695	pathogenic-leaning
SaProt	LLR -11.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: EDAR
Protein: p.Ala378Val
Coding: c.1133C>T
MANE Select: NM_022336
dbSNP: rs2105371700
Type: single nucleotide variant
Location: chr2:108897121 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB
Residue 378: the death domain

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

Disease context

EDAR-related disorder

Also linked: ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Similar variants

EDAR p.Ala378Thr Pathogenic ★ same residue
EDAR p.Ala26Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EDAR p.Arg25Ter Pathogenic/Likely pathogenic ★★ same condition
EDAR p.Arg358Ter Pathogenic ★★ same condition
EDAR p.Arg420Gln Pathogenic/Likely pathogenic ★★ same condition
EDAR p.Arg89His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EDAR p.Arg98Trp Pathogenic/Likely pathogenic ★★ same condition
EDAR p.Cys301Ter 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/edar-p-ala378val (accessed [today's date]).

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