EDAR

Summary

EDAR (ectodysplasin A receptor, HGNC:2895) is a protein-coding gene on chromosome 2q13, encoding Tumor necrosis factor receptor superfamily member EDAR (Q9UNE0). Receptor for EDA isoform A1, but not for EDA isoform A2.

This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia.

Source: NCBI Gene 10913 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 369 total — 49 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_022336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2895
Approved symbol	EDAR
Name	ectodysplasin A receptor
Location	2q13
Locus type	gene with protein product
Status	Approved
Aliases	ED5, EDA3, ED1R, EDA1R
Ensembl gene	ENSG00000135960
Ensembl biotype	protein_coding
OMIM	604095
Entrez	10913

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000258443, ENST00000376651, ENST00000409271, ENST00000970167

RefSeq mRNA: 1 — MANE Select: NM_022336 NM_022336

CCDS: CCDS2081

Canonical transcript exons

ENST00000258443 — 12 exons

Exon	Start	End
ENSE00000804455	108906308	108906368
ENSE00000804456	108907860	108908019
ENSE00000804458	108910776	108910850
ENSE00000804459	108910947	108911072
ENSE00000804460	108912678	108912764
ENSE00001009441	108929198	108929379
ENSE00001009443	108923368	108923453
ENSE00001009447	108930120	108930242
ENSE00001260366	108910460	108910532
ENSE00001260420	108930964	108931032
ENSE00001582048	108894471	108897229
ENSE00003842673	108988960	108989220

Expression profiles

Bgee: expression breadth broad, 100 present calls, max score 97.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3358 / max 52.4438, expressed in 116 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30097	0.2101	62
30094	0.0576	22
30096	0.0322	9
30092	0.0176	5
30095	0.0141	4
30093	0.0042	1

Top tissues by expression

247 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.14	gold quality
oocyte	CL:0000023	92.11	gold quality
pancreatic ductal cell	CL:0002079	80.04	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.76	gold quality
esophagus squamous epithelium	UBERON:0006920	75.15	gold quality
tibialis anterior	UBERON:0001385	71.92	silver quality
epithelium of esophagus	UBERON:0001976	71.57	gold quality
epithelial cell of pancreas	CL:0000083	70.57	silver quality
esophagus mucosa	UBERON:0002469	70.16	gold quality
oral cavity	UBERON:0000167	69.01	gold quality
lower esophagus mucosa	UBERON:0035834	68.30	gold quality
endothelial cell	CL:0000115	67.84	gold quality
epithelium of nasopharynx	UBERON:0001951	67.73	gold quality
squamous epithelium	UBERON:0006914	67.56	gold quality
ileal mucosa	UBERON:0000331	66.47	gold quality
skin of hip	UBERON:0001554	66.41	gold quality
rectum	UBERON:0001052	66.20	gold quality
mucosa of urinary bladder	UBERON:0001259	65.93	silver quality
olfactory bulb	UBERON:0002264	65.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.36	silver quality
upper leg skin	UBERON:0004262	63.81	gold quality
jejunal mucosa	UBERON:0000399	62.63	silver quality
duodenum	UBERON:0002114	62.21	gold quality
lymph node	UBERON:0000029	61.93	gold quality
pharyngeal mucosa	UBERON:0000355	61.89	gold quality
buccal mucosa cell	CL:0002336	61.76	gold quality
periodontal ligament	UBERON:0008266	61.67	gold quality
germinal epithelium of ovary	UBERON:0001304	61.55	silver quality
gingival epithelium	UBERON:0001949	60.45	gold quality
skin of leg	UBERON:0001511	60.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting EDAR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Literature-anchored findings (GeneRIF, showing 40)

• isoforms of EDA-A5 and A5’,activated NF-kappaB through receptors EDAR and XEDAR (PMID:16423472)
• EDAR mutations account for one-quarter of non-ED1-related hypohidrotic ectodermal dyspl (PMID:16435307)
• novel deletion mutation in a Pakistani family with autosomal recessive hypohidrotic ectodermal dysplasia (PMID:17501952)
• study reports the molecular analyses of four patients from India with hypohidrotic ectodermal dysplasia, three who harbour novel mutations, two in the EDA gene and one in the EDAR gene (PMID:17970812)
• EDAR is a major genetic determinant of Asian hair thickness and the 1540C allele spread through Asian populations due to recent positive selection (PMID:18065779)
• Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype of hypohidrotic ectodermal dysplasia than those with a heterozygous missense, nonsense or frame-shift mutation (PMID:18231121)
• Study shows that the derived EDAR370A common in East Asia has a more potent signaling output than the ancestral EDAR370 V; shows that elevation of Edar activity in transgenic mice converts their hair phenotype to the typical East Asian morphology. (PMID:18561327)
• EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations. (PMID:18704500)
• results expand the allelic series for mutations underlying hypohidrotic ectodermal dysplasia (PMID:19438931)
• Recurrent mutations in functionally-related EDA and EDAR genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia. (PMID:19551394)
• an EDAR variant is a genetic determinant of shovel-shaped incisors (PMID:19804850)
• a novel compound heterozygous mutation [c.52-2A>G; c.212G>A (p.Cys71Tyr)]; significance of the EDAR signalling pathway in the ectodermal morphogenesis. (PMID:20033817)
• DNA sequence analysis of EDAR gene in a Pakistani family, demonstrating autosomal recessive form of hypohidrotic ectodermal dysplasia, identified a novel homozygous mutation affecting splice donor site of exon 5 [IVS5+1G > or = C] of the gene (PMID:20199431)
• Data show that 25 different mutations on EDA and EDAR genes were detected in HED patients. (PMID:20236127)
• WNT10A and EDAR were each responsible for 16% of hypohidrotic/anhidrotic ectodermal dysplasia cases. (PMID:20979233)
• screening of all the 12 exons and splice junctions of gene EDAR revealed a novel missense mutation (c.1163T>C; p.Ile388Thr) in family A and a novel insertion mutation (c.1014insA; p.V339SfsX6) in family B. (PMID:21771270)
• This is the first report of a founder EDAR mutation and of a significantly high frequency of autosomal recessive HED. (PMID:22032522)
• Using whole-exome sequencing we describe a novel homozygous missense mutation in EDAR causing autosomal recessive HED associated with palmoplantar hyperkeratosis and the absence of breasts. (PMID:23210707)
• Study generated a knockin mouse model and found that, as in humans, hair thickness is increased in EDAR370A mice; new biological targets affected by the mutation were identified, including mammary and eccrine glands. Building on these results EDAR370A was found to be associated with an increased number of active eccrine glands in the Han Chinese. (PMID:23415220)
• we have identi fi ed a novel frameshift mutation in an Italian family with autosomal dominant hypohidrotic ectodermal dysplasia resulting in a mild clinical phenotype. (PMID:24641098)
• Confirmed that EDARV370A, a variant that first originated in East Asia about 30000 years ago, played an important role in incisor shoveling in East Asia. This suggests that incisor shoveling in modern East Asians appeared after the late Pleistocene. (PMID:24752358)
• Individuals with a c.1072C > T mutation in the EDAR-gene displayed a typical pattern of congenitally missing teeth in the frontal area with functional consequences. (PMID:24884697)
• Four traits of ear pinna anatomic variation are associated with a functional variant in the EDAR gene, a key regulator of embryonic skin appendage development. (PMID:26105758)
• Individuals with a c.1072C > T mutation in the EDAR-gene displayed more hair shaft deformations confirming the role of EDAR for human hair follicle development and postnatal hair follicle cycling. (PMID:26336973)
• Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development (PMID:26603699)
• To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 x 10(-12)) and TCHH (rs11803731: P = 1.46 x 10(-3)) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). (PMID:27487801)
• EDAR was sequenced in hypohidrotic ectodermal dysplasia patients negative for EDA mutations. The EDAR exon 12 variant rs3827760 (T>C, p.V370A) was analysed for a possible additive effect (PMID:28045201)
• 10 and five quantitative trait-associated mutations for oxygen saturation (SaO2) and blood platelet count, respectively, are identified at the Edar Receptor (EDAR) locus. rs10865026 and rs3749110 (associated with SaO2 and platelet count, respectively) are functional candidate targets. EDAR has undergone natural selection in recent human history and EDAR variants has an important role in Tibetan high-altitude adaptations. (PMID:28795375)
• Results suggested that SNPs in EDAR could be a pathogenic factor for non-syndromic tooth agenesis. Furthermore, EDAR can be regarded as a marker gene for the risk of tooth agenesis. (PMID:28808699)
• Authors report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-kappaB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. (PMID:29855541)
• The analysis identified significant association (P<0.05 after multiple testing correction) between EDAR V370A mutation and eight facial phenotypes, one chin phenotype and three ear morphology phenotypes. (PMID:30465535)
• Study in HEK293 cells showed that mutant EDAR completely lost its affinity to EDARADD and suppressed the downstream NFkappa-B activation induced by wild-type EDAR in a dominant-negative manner. Mutant EDAR was capable of binding with the wild-type EDAR, which led to reduced interaction between the wild-type EDAR and EDARADD disclosing, in part, the molecular basis of autosomal dominant hypohidrotic ectodermal dysplasia. (PMID:31245878)
• The identification of the same homozygous mutation segregating with disease in two different families supports the important role of the gene in the development of the disorder and this may contribute to novel approaches, prenatal diagnosis and genetic counseling of families with EDAR related disorders. (PMID:31310406)
• The p.Trp434Gly substitution of EDAR might be a loss-of-function alteration that would significantly alter its affinity to EDARADD, and finally, influence the downstream activation of NF-kappa B. (PMID:31652981)
• study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in Hypohidrotic ectodermal dysplasia and 44.4% in non-syndromic tooth agenesis. (PMID:31796081)
• Novel EDAR mutation in tooth agenesis and variable associated features. (PMID:32325225)
• Characterisation of a second gain of function EDAR variant, encoding EDAR380R, in East Asia. (PMID:32499598)
• Homozygous variants of EDAR underlying hypohidrotic ectodermal dysplasia in three consanguineous families. (PMID:32819890)
• Comparative analysis of rare EDAR mutations and tooth agenesis pattern in EDAR- and EDA-associated nonsyndromic oligodontia. (PMID:32906216)
• Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis. (PMID:33205897)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	edar	ENSDARG00000099088
mus_musculus	Edar	ENSMUSG00000003227
rattus_norvegicus	Edar	ENSRNOG00000028598

Paralogs (2): TNFRSF19 (ENSG00000127863), EDA2R (ENSG00000131080)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member EDAR — Q9UNE0 (reviewed: Q9UNE0)

Alternative names: Anhidrotic ectodysplasin receptor 1, Downless homolog, EDA-A1 receptor, Ectodermal dysplasia receptor, Ectodysplasin-A receptor

All UniProt accessions (1): Q9UNE0

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for EDA isoform A1, but not for EDA isoform A2. Mediates the activation of NF-kappa-B and JNK. May promote caspase-independent cell death.

Subunit / interactions. Binds to EDARADD. Associates with TRAF1, TRAF2, TRAF3 and NIK.

Subcellular location. Membrane.

Tissue specificity. Detected in fetal kidney, lung, skin and cultured neonatal epidermal keratinocytes. Not detected in lymphoblast and fibroblast cell lines.

Disease relevance. Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (ECTD10A) [MIM:129490] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is an autosomal dominant condition characterized by hypotrichosis, abnormal or missing teeth, and hypohidrosis due to the absence of sweat glands. The disease is caused by variants affecting the gene represented in this entry. Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (ECTD10B) [MIM:224900] A disorder due to abnormal development of two or more ectodermal structures, and characterized by sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth and the inability to sweat due to the absence of sweat glands. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variation in EDAR is associated with variations in head hair thickness and defines the hair morphology locus 1 (HRM1) [MIM:612630]. Besides skin color and facial features, hair morphology is one of the most distinctive traits among human populations, and classical classification of human population is based on such visible traits.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNE0-1	1	yes
Q9UNE0-2	2

RefSeq proteins (1): NP_071731* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR034052	EDAR_N	Domain
IPR047526	TNR19/27/EDAR	Family
IPR056762	Death_EDAR	Domain

Pfam: PF24979

UniProt features (50 total): sequence variant 20, disulfide bond 6, strand 5, sequence conflict 3, repeat 3, compositionally biased region 2, topological domain 2, signal peptide 1, chain 1, glycosylation site 1, splice variant 1, transmembrane region 1, mutagenesis site 1, helix 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7X9G	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNE0-F1	67.01	0.14

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (6): 31–44, 47–60, 50–71, 74–87, 93–113, 135–148

Glycosylation sites (1): 38

Mutagenesis-validated functional residues (1):

Position	Phenotype
379	reduces activation of nf-kappa-b.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors

MSigDB gene sets: 217 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SALIVARY_GLAND_DEVELOPMENT, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TATTATA_MIR374, GOBP_PIGMENTATION, AGTCTTA_MIR499, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_JNK_CASCADE, TCF11_01

GO Biological Process (12): hair follicle development (GO:0001942), apoptotic process (GO:0006915), epidermis development (GO:0008544), positive regulation of gene expression (GO:0010628), cytokine-mediated signaling pathway (GO:0019221), cell differentiation (GO:0030154), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), pigmentation (GO:0043473), positive regulation of JNK cascade (GO:0046330), salivary gland cavitation (GO:0060662), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), apical part of cell (GO:0045177)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of intracellular signal transduction	2
cellular anatomical structure	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
tissue development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cellular developmental process	1
odontogenesis	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
biological_process	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
salivary gland morphogenesis	1
tube lumen cavitation	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
signaling receptor activity	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDAR	EDA	Q92838	999
EDAR	EDARADD	Q8WWZ3	989
EDAR	SLC24A5	Q71RS6	903
EDAR	SLC45A2	Q9UMX9	836
EDAR	TNF	P01375	716
EDAR	WNT10A	Q9GZT5	710
EDAR	SHH	Q15465	705
EDAR	TNFRSF1A	P19438	700
EDAR	CYLD	Q9NQC7	692
EDAR	LEF1	Q9UJU2	677
EDAR	PAX9	P55771	675
EDAR	TRAF6	Q9Y4K3	662
EDAR	IKBKG	Q9Y6K9	644
EDAR	BMP4	P12644	622
EDAR	DKK4	Q9UBT3	616

IntAct

12 interactions, top by confidence:

A	B	Type	Score
EDA	EDAR	psi-mi:“MI:0915”(physical association)	0.590
EDAR	EDA	psi-mi:“MI:0915”(physical association)	0.590
EDAR	Traf1	psi-mi:“MI:0915”(physical association)	0.400
EDAR	Traf2	psi-mi:“MI:0915”(physical association)	0.400
EDAR	TRAF3	psi-mi:“MI:0915”(physical association)	0.400
MAP3K14	EDAR	psi-mi:“MI:0915”(physical association)	0.400
EDAR	LILRB1	psi-mi:“MI:0915”(physical association)	0.400
EDAR	EDARADD	psi-mi:“MI:0915”(physical association)	0.400
EDAR	UPK3BL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): EDAR (Affinity Capture-MS), EDAR (Two-hybrid), EDAR (Two-hybrid), ZNF624 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), ABCC4 (Affinity Capture-MS), EDARADD (Reconstituted Complex), BMPR1A (Affinity Capture-MS), IFNGR1 (Affinity Capture-MS), UBL3 (Affinity Capture-MS), LRP10 (Affinity Capture-MS), ACVR1 (Affinity Capture-MS), NDFIP2 (Affinity Capture-MS), STK16 (Affinity Capture-MS), ZC3H3 (Affinity Capture-MS)

ESM2 similar proteins: A2AR95, D5K8A9, E7FEC4, F1LW30, F1NUK7, O62802, O70535, O95256, O95727, P01589, P01590, P12342, P22934, P26897, P26898, P27931, P40200, P41690, P42702, P42703, P43303, P80370, Q03472, Q149L7, Q38IC8, Q3SXY7, Q5DTZ6, Q5MNY4, Q5XNR9, Q60736, Q61521, Q64735, Q6GMZ9, Q6UXZ4, Q7T2L7, Q7TSY4, Q86YD5, Q8BGE4, Q8BX35, Q8K1S2

Diamond homologs: Q90VY2, Q9JLL3, Q9N092, Q9NS68, Q9R187, Q9UNE0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EDA	up-regulates	EDAR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

369 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	31
Uncertain significance	160
Likely benign	37
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075576	NM_022336.4(EDAR):c.964-1G>A	Pathogenic
1175106	NM_022336.4(EDAR):c.964-1G>C	Pathogenic
1452944	NM_022336.4(EDAR):c.1097_1098del (p.Asn365_Ser366insTer)	Pathogenic
1721247	NM_022336.4(EDAR):c.1292T>C (p.Ile431Thr)	Pathogenic
194115	NM_022336.4(EDAR):c.1144G>A (p.Gly382Ser)	Pathogenic
2052298	NM_022336.4(EDAR):c.1297G>T (p.Glu433Ter)	Pathogenic
2075534	NM_022336.4(EDAR):c.293G>A (p.Arg98Gln)	Pathogenic
228341	NC_000002.12:g.(?108910426)(108912698_?)del	Pathogenic
265113	NM_022336.4(EDAR):c.212G>A (p.Cys71Tyr)	Pathogenic
2944544	NM_022336.4(EDAR):c.1221del (p.Ser407fs)	Pathogenic
2946816	NM_022336.4(EDAR):c.641dup (p.Pro215fs)	Pathogenic
2948715	NM_022336.4(EDAR):c.1024+2T>C	Pathogenic
2950142	NM_022336.4(EDAR):c.1280T>C (p.Leu427Ser)	Pathogenic
2952436	NM_022336.4(EDAR):c.931del (p.Glu311fs)	Pathogenic
2952572	NM_022336.4(EDAR):c.1218C>G (p.Tyr406Ter)	Pathogenic
3247228	NC_000002.11:g.(?109513363)(109524495_?)del	Pathogenic
3341133	NM_022336.4(EDAR):c.346T>C (p.Cys116Arg)	Pathogenic
3391811	NM_022336.4(EDAR):c.730+1G>T	Pathogenic
3756461	NM_022336.4(EDAR):c.1024+1G>T	Pathogenic
3759646	NM_022336.4(EDAR):c.1090del (p.Tyr364fs)	Pathogenic
417939	NM_022336.4(EDAR):c.284del (p.Gly95fs)	Pathogenic
419158	NM_022336.4(EDAR):c.883_889delinsTGATGAGGAGCCCG (p.Gln295_Ser297delinsTer)	Pathogenic
431815	NM_022336.4(EDAR):c.442+1G>A	Pathogenic
449014	NM_022336.4(EDAR):c.903C>A (p.Cys301Ter)	Pathogenic
463874	NM_022336.4(EDAR):c.1024+1G>A	Pathogenic
463876	NM_022336.4(EDAR):c.1132G>A (p.Ala378Thr)	Pathogenic
4786258	NM_022336.4(EDAR):c.983del (p.Lys328fs)	Pathogenic
4789004	NM_022336.4(EDAR):c.757del (p.Asp253fs)	Pathogenic
504887	NM_022336.4(EDAR):c.529+1G>A	Pathogenic
522911	NM_022336.4(EDAR):c.278G>C (p.Cys93Ser)	Pathogenic

SpliceAI

1743 predictions. Top by Δscore:

Variant	Effect	Δscore
2:108897228:ACCTA:A	acceptor_loss	1.0000
2:108897230:CTAC:C	acceptor_loss	1.0000
2:108906302:GCTTA:G	donor_loss	1.0000
2:108906303:CTTAC:C	donor_loss	1.0000
2:108906304:TTACC:T	donor_loss	1.0000
2:108906305:TA:T	donor_loss	1.0000
2:108907892:C:CA	donor_gain	1.0000
2:108908015:TCTCG:T	acceptor_gain	1.0000
2:108908016:CTCG:C	acceptor_gain	1.0000
2:108908016:CTCGC:C	acceptor_gain	1.0000
2:108908017:TCG:T	acceptor_gain	1.0000
2:108908017:TCGC:T	acceptor_loss	1.0000
2:108908017:TCGCT:T	acceptor_gain	1.0000
2:108908018:CG:C	acceptor_gain	1.0000
2:108908018:CGC:C	acceptor_gain	1.0000
2:108908019:GC:G	acceptor_loss	1.0000
2:108908020:C:CC	acceptor_gain	1.0000
2:108908020:CTGCA:C	acceptor_loss	1.0000
2:108910455:CATA:C	donor_loss	1.0000
2:108910456:ATACC:A	donor_loss	1.0000
2:108910457:TAC:T	donor_loss	1.0000
2:108910458:A:AC	donor_gain	1.0000
2:108910459:C:CA	donor_loss	1.0000
2:108910459:C:CC	donor_gain	1.0000
2:108910459:CCT:C	donor_gain	1.0000
2:108910528:GTTGT:G	acceptor_gain	1.0000
2:108910529:TTGT:T	acceptor_gain	1.0000
2:108910530:TGT:T	acceptor_gain	1.0000
2:108910531:GT:G	acceptor_gain	1.0000
2:108910531:GTC:G	acceptor_loss	1.0000

AlphaMissense

2931 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:108897010:A:G	L415P	1.000
2:108897022:A:G	L411P	1.000
2:108897121:G:T	A378D	1.000
2:108897124:A:G	L377P	1.000
2:108897134:A:G	W374R	1.000
2:108897134:A:T	W374R	1.000
2:108929295:A:G	C87R	1.000
2:108896995:C:G	R420P	0.999
2:108897019:A:G	L412P	0.999
2:108897055:C:G	R400P	0.999
2:108897064:A:G	L397P	0.999
2:108897106:A:G	L383P	0.999
2:108897122:C:G	A378P	0.999
2:108897130:C:G	R375P	0.999
2:108897132:C:A	W374C	0.999
2:108897132:C:G	W374C	0.999
2:108897175:A:G	L360P	0.999
2:108897175:A:T	L360H	0.999
2:108897211:A:G	L348P	0.999
2:108923405:G:C	C135W	0.999
2:108923407:A:G	C135R	0.999
2:108929208:A:G	C116R	0.999
2:108929216:C:G	C113S	0.999
2:108929217:A:G	C113R	0.999
2:108929217:A:T	C113S	0.999
2:108929276:C:G	C93S	0.999
2:108929276:C:T	C93Y	0.999
2:108929277:A:T	C93S	0.999
2:108929293:G:C	C87W	0.999
2:108929294:C:G	C87S	0.999

dbSNP variants (sampled 300 via entrez): RS1000010939 (2:108965575 G>A), RS1000026494 (2:108931525 A>C), RS1000038233 (2:108926193 G>A), RS1000042219 (2:108981266 A>C,G), RS1000132701 (2:108930898 C>A), RS1000139888 (2:108925906 G>A,C,T), RS1000199835 (2:108898105 A>G), RS1000207366 (2:108914899 C>T), RS1000213505 (2:108937041 G>A,T), RS1000264373 (2:108978612 T>G), RS1000268864 (2:108931169 A>G), RS1000282082 (2:108904437 A>G), RS1000287571 (2:108965951 C>A), RS1000399170 (2:108904649 T>C), RS1000541194 (2:108949280 C>A)

Disease associations

OMIM: gene MIM:604095 | disease phenotypes: MIM:129490, MIM:224900, MIM:305100, MIM:203700, MIM:613662, MIM:614941, MIM:608033

GenCC curated gene-disease

Disease	Classification	Inheritance
ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive	Definitive	Autosomal recessive
ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant	Strong	Autosomal dominant
hypohidrotic ectodermal dysplasia	Strong	Semidominant
autosomal dominant hypohidrotic ectodermal dysplasia	Supportive	Autosomal dominant
autosomal recessive hypohidrotic ectodermal dysplasia	Supportive	Autosomal recessive

Mondo (10): ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (MONDO:0007509), autosomal recessive hypohidrotic ectodermal dysplasia (MONDO:0016619), ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (MONDO:0009147), hypohidrotic ectodermal dysplasia (MONDO:0016535), autosomal dominant hypohidrotic ectodermal dysplasia (MONDO:0015884), ectodermal dysplasia syndrome (MONDO:0019287), mitochondrial DNA depletion syndrome 4a (MONDO:0008758), mitochondrial DNA depletion syndrome 4b (MONDO:0013350), ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive (MONDO:0013983), familial acute necrotizing encephalopathy (MONDO:0011953)

Orphanet (7): Autosomal dominant hypohidrotic ectodermal dysplasia (Orphanet:1810), Hypohidrotic ectodermal dysplasia (Orphanet:238468), Autosomal recessive hypohidrotic ectodermal dysplasia (Orphanet:248), Ectodermal dysplasia syndrome (Orphanet:79373), Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet:298), Alpers-Huttenlocher syndrome (Orphanet:726), Familial acute necrotizing encephalopathy (Orphanet:88619)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000457	Depressed nasal ridge
HP:0000607	Periorbital wrinkles
HP:0000653	Sparse eyelashes
HP:0000668	Hypodontia
HP:0000674	Anodontia
HP:0000677	Oligodontia
HP:0000685	Hypoplasia of teeth
HP:0000691	Microdontia
HP:0000698	Conical tooth
HP:0000958	Dry skin
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis
HP:0000966	Hypohidrosis
HP:0000968	Ectodermal dysplasia
HP:0000970	Anhidrosis
HP:0001000	Abnormality of skin pigmentation
HP:0001106	Periorbital hyperpigmentation
HP:0001231	Abnormal fingernail morphology
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001807	Ridged nail
HP:0002007	Frontal bossing
HP:0002046	Heat intolerance
HP:0002047	Malignant hyperthermia
HP:0002213	Fine hair
HP:0002217	Slow-growing hair

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST002994_3	Ear protrusion	1.000000e-10
GCST002997_1	Helix rolling	1.000000e-12
GCST002998_1	Lobe attachment	2.000000e-09
GCST002999_1	Lobe size	1.000000e-12
GCST003001_2	Ear morphology	1.000000e-11
GCST003474_7	Scalp hair shape	3.000000e-119
GCST003475_4	Beard thickness	1.000000e-15
GCST003477_5	Monobrow thickness	1.000000e-07
GCST003636_1	lower facial morphology traits (quantitative measurement)	4.000000e-10
GCST003983_39	Male-pattern baldness	1.000000e-08
GCST003996_43	Monobrow	2.000000e-15
GCST005193_16	Lobe attachment (rater scored)	7.000000e-10
GCST005653_2	Cleft lip with or without cleft palate (maternal periconceptional alcohol intake interaction)	4.000000e-07
GCST006093_1	Thick vs thin eyebrows	2.000000e-09
GCST006094_1	Straight vs curly hair	2.000000e-103
GCST006468_1	Straight vs curly hair	2.000000e-12
GCST006468_2	Straight vs curly hair	5.000000e-16
GCST006483_26	Lung function (FVC)	2.000000e-08
GCST006585_1678	Blood protein levels	5.000000e-59
GCST006706_2	Eyebrow thickness	6.000000e-11
GCST010736_3	Urinary albumin-to-creatinine ratio	2.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007665	ear protrusion
EFO:0007670	helix rolling
EFO:0007667	lobe attachment
EFO:0007666	lobe size
EFO:0007664	outer ear morphology trait
EFO:0007906	synophrys measurement
EFO:0003959	cleft lip
EFO:0009113	alcohol exposure measurement
EFO:0005038	hair morphology
EFO:0004312	vital capacity
EFO:0007778	urinary albumin to creatinine ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D053360	Ectodermal Dysplasia, Hypohidrotic, Autosomal Recessive	C16.131.077.350.348; C16.131.831.350.348; C16.320.850.250.348; C17.800.804.350.348; C17.800.827.250.348

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250376 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Tumour necrosis factor (TNF) receptor family

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation, affects cotreatment, decreases expression, increases abundance	3
(+)-JQ1 compound	decreases expression	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	decreases expression	1
Methapyrilene	increases methylation	1
Quercetin	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1250032	Binding	Binding affinity to human Ectodysplasin-A receptor by surface plasmon resonance method	C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. — Nat Chem Biol

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1RY	HyCyte MKN45 KO-hEDAR	Cancer cell line	Female

Clinical trials (associated diseases)

19 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01109290	Not specified	COMPLETED	Characterization of Sweat Gland Function in Patients With Recessively Inherited Hypohidrotic Ectodermal Dysplasia
NCT01293565	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected by Hypohidrotic Ectodermal Dysplasia - A
NCT01386775	Not specified	COMPLETED	Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia: Intrafamilial Variation
NCT01398397	Not specified	COMPLETED	Medical Record Review of Hypohidrotic Ectodermal Dysplasia Clinical Phenotype
NCT01398813	Not specified	COMPLETED	X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Carrier Outlook Toward Reproduction Survey
NCT01629927	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia (ECP-012)
NCT01629940	Not specified	COMPLETED	Phenotypic and Genetic Properties in Males at Risk for X-linked Hypohidrotic Ectodermal Dysplasia: Evaluation of an Early Diagnosis Technology and Tests to Assess Nutritional Status
NCT04741412	Not specified	COMPLETED	Pediatric SARS-CoV-2 Infections: Course of COVID-19, Immune Responses, Complications and Long-term Consequences
NCT05378932	Not specified	COMPLETED	Impact of Dysregulation of Core Body Temperature on Sleep in Patients With Hypohidrotic Ectodermal Dysplasia
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT03034512	Not specified	TERMINATED	Alpers Huttenlocher Natural History Study