Is EDAR p.Val370Ala (c.1109T>C) pathogenic?

EDAR p.Val370Ala (c.1109T>C) is classified Benign in EDAR (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.6212); Common (popmax 84.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive hypohidrotic ectodermal dysplasia.

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.Val370Ala (c.1109T>C)?

AlphaMissense predicts likely pathogenic (score 0.6212) — an in-silico prediction, not a clinical call.

EDAR p.Val370Ala

Q: What condition is associated with EDAR p.Val370Ala (c.1109T>C)?

EDAR p.Val370Ala (c.1109T>C) is associated with autosomal recessive hypohidrotic ectodermal dysplasia, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (ClinVar).

Q: How common is EDAR p.Val370Ala (c.1109T>C) in the general population?

EDAR p.Val370Ala (c.1109T>C) is common (popmax 84.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1109T>C · rs3827760 · VCV5858

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6212 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 84.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
AlphaMissense	0.6212	likely pathogenic
REVEL	0.47	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	24.2	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 84.5% East Asian · 37,894/44,840 alleles

Filtering AF 83.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 83.5%

Overall 4.95% 79,887/1,613,832 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	84.5%	1
Admixed American	42.9%	2
Remaining individualsnot grpmax-eligible	6.61%	15
Finnishnot grpmax-eligible	5.55%	18
Ashkenazi Jewishnot grpmax-eligible	1.72%	58
African / African-American	1.1%	91
South Asian	0.977%	102
Middle Eastern	0.841%	119
European (non-Finnish)	0.532%	188

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.Val370Ala
Coding: c.1109T>C
MANE Select: NM_022336
dbSNP: rs3827760
Type: single nucleotide variant
Location: chr2:108897145 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB
Residue 370: a UniProt-annotated variant site (associated with increase in hair thickness; results in decreased downstream activity of nfkb1 48 hours after transfection into cells); a UniProt-annotated variant site (in); the death domain

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 ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive 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 c.730+1G>T Pathogenic ★★ same condition
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.Cys148Arg 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-val370ala (accessed [today's date]).

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