Is EDAR p.Val203Ile (c.607G>A) pathogenic?

EDAR p.Val203Ile (c.607G>A) is classified Uncertain significance in EDAR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-08). AlphaMissense: likely benign (0.1325); Ultra-rare (popmax 0.0392%, nfe); Associated with ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant.

What condition is associated with EDAR p.Val203Ile (c.607G>A)?

EDAR p.Val203Ile (c.607G>A) is associated with ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, hypohidrotic ectodermal dysplasia, autosomal recessive hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDAR p.Val203Ile (c.607G>A) in the general population?

EDAR p.Val203Ile (c.607G>A) is ultra-rare (popmax 0.0392%, nfe) (gnomAD).

What do computational predictors say about EDAR p.Val203Ile (c.607G>A)?

AlphaMissense predicts likely benign (score 0.1325) — an in-silico prediction, not a clinical call.

EDAR p.Val203Ile

c.607G>A · rs148212997 · VCV330709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1325	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -6.09	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 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0392% European (non-Finnish) · 463/1,180,000 alleles

Filtering AF 0.0363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0312% 504/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0392%	2,549
African / African-American	0.0387%	2,583
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00439%	22,770
East Asian	0.00223%	44,876
Finnishnot grpmax-eligible	0.00156%	64,028

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.Val203Ile
Coding: c.607G>A
MANE Select: NM_022336
dbSNP: rs148212997
Type: single nucleotide variant
Location: chr2:108910995 (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

ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypohidrotic ectodermal dysplasia autosomal recessive hypohidrotic ectodermal dysplasia

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-val203ile (accessed [today's date]).

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