Is EDAR p.Leu43= (c.129G>A) pathogenic?

EDAR p.Leu43= (c.129G>A) is classified Likely benign in EDAR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-10-26). Very rare (popmax 0.00133%, afr); Associated with EDAR-related disorder.

What condition is associated with EDAR p.Leu43= (c.129G>A)?

EDAR p.Leu43= (c.129G>A) is associated with EDAR-related disorder (ClinVar).

How common is EDAR p.Leu43= (c.129G>A) in the general population?

EDAR p.Leu43= (c.129G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

EDAR p.Leu43=

c.129G>A · rs1294790173 · VCV3029666

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 1.4	GERP 0.47, phastCons 1
Overall
CADD	8.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Overall 0.000248% 4/1,613,958 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,310
African / African-Americangrpmax	0.00133%	74,932

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu43=
Coding: c.129G>A
MANE Select: NM_022336
dbSNP: rs1294790173
Type: single nucleotide variant
Location: chr2:108930165 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB
Residue 43: a disulfide bond

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.Leu43fs Likely pathogenic ★ same residue
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.Ala446= 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-leu43 (accessed [today's date]).

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