Is EDAR p.Ala446= (c.1338T>A) pathogenic?

EDAR p.Ala446= (c.1338T>A) is classified Likely benign in EDAR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-12). Very rare (popmax 0.00017%, nfe); Associated with EDAR-related disorder.

What condition is associated with EDAR p.Ala446= (c.1338T>A)?

EDAR p.Ala446= (c.1338T>A) is associated with EDAR-related disorder (ClinVar).

How common is EDAR p.Ala446= (c.1338T>A) in the general population?

EDAR p.Ala446= (c.1338T>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

EDAR p.Ala446=

c.1338T>A · rs192939679 · VCV3039813

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

EDAR-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.6
Overall
CADD	0.391	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,252 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,611,922 alleles · very rare exomes 0/1,459,746 · genomes 2/152,176 · joint denominator

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: EDAR
Protein: p.Ala446=
Coding: c.1338T>A
MANE Select: NM_022336
dbSNP: rs192939679
Type: single nucleotide variant
Location: chr2:108896916 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB

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

Disease context

EDAR-related disorder

Similar variants

EDAR p.Arg358Ter Pathogenic ★★ same condition
EDAR p.Arg420Gln Pathogenic/Likely pathogenic ★★ same condition
EDAR p.Ala24Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
EDAR p.Ala378Val Uncertain significance ★ ⚠ same condition
EDAR p.Lys252Arg Uncertain significance ★ ⚠ same condition
EDAR p.Cys135Tyr Pathogenic same condition
EDAR p.Leu43= Likely benign same condition
EDAR p.Leu432= Likely benign 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-ala446 (accessed [today's date]).

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