Is EDAR p.Val246Met (c.736G>A) pathogenic?

EDAR p.Val246Met (c.736G>A) is classified Benign in EDAR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1178); Low-frequency (popmax 3.33%, afr); Associated with autosomal recessive hypohidrotic ectodermal dysplasia.

What condition is associated with EDAR p.Val246Met (c.736G>A)?

EDAR p.Val246Met (c.736G>A) is associated with autosomal recessive hypohidrotic ectodermal dysplasia, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDAR p.Val246Met (c.736G>A) in the general population?

EDAR p.Val246Met (c.736G>A) is low-frequency (popmax 3.33%, afr) (gnomAD).

How is Hypohidrotic ectodermal dysplasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EDAR p.Val246Met (c.736G>A)?

AlphaMissense predicts likely benign (score 0.1178) — an in-silico prediction, not a clinical call.

EDAR p.Val246Met

c.736G>A · rs79798733 · VCV702179

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1178 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.33%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.1178	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	25.7	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 3.33% African / African-American · 2,498/74,986 alleles

Filtering AF 3.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.18%

Overall 0.172% 2,779/1,612,712 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.33%	30
Remaining individualsnot grpmax-eligible	0.231%	434
Middle Eastern	0.165%	606
Admixed American	0.145%	690
South Asian	0.00879%	11,371
European (non-Finnish)	0.00271%	36,840

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.Val246Met
Coding: c.736G>A
MANE Select: NM_022336
dbSNP: rs79798733
Type: single nucleotide variant
Location: chr2:108910527 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB
Residue 246: the 'disordered' region

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

Disease context

autosomal recessive hypohidrotic ectodermal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Hypohidrotic ectodermal dysplasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
EDAR p.Cys428Arg Pathogenic/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/edar-p-val246met (accessed [today's date]).

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