Alopecia universalis congenita

Summary

Alopecia universalis congenita (MONDO:0008757) is a disease caused by HR (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: HR (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 176
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	25	Europe	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000561	Absent eyelashes	Very frequent (80-99%)
HP:0002223	Absent eyebrow	Very frequent (80-99%)
HP:0002232	Patchy alopecia	Very frequent (80-99%)
HP:0002289	Alopecia universalis	Very frequent (80-99%)
HP:0000820	Abnormality of the thyroid gland	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001047	Atopic dermatitis	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0003119	Abnormal circulating lipid concentration	Occasional (5-29%)
HP:0001045	Vitiligo	Very rare (<1-4%)
HP:0003765	Psoriasiform dermatitis	Very rare (<1-4%)
HP:0100651	Type I diabetes mellitus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alopecia universalis congenita
Mondo ID	MONDO:0008757
MeSH	C537055
OMIM	203655
Orphanet	701
DOID	DOID:0050634
SNOMED CT	86166000
UMLS	C1859877
MedGen	349262
GARD	0000614
MedDRA	10001767
Is cancer (heuristic)	no

Also known as: alopecia areata universalis · alopecia universalis congenita · ALUNC · atrichia, generalised · atrichia, generalized · AU

Data availability: 176 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › alopecia › alopecia, isolated › alopecia universalis congenita

Related subtypes (7): alopecia areata 1, familial focal alopecia, alopecia, androgenetic, 1, alopecia, congenital, alopecia, androgenetic, 2, alopecia areata 2, alopecia, androgenetic, 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

176 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 41 benign, 18 conflicting classifications of pathogenicity, 11 benign/likely benign, 5 pathogenic, 5 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687272	NM_005144.5(HR):c.2541G>A (p.Trp847Ter)	HR	Pathogenic	criteria provided, single submitter
4709573	NM_005144.5(HR):c.2818C>T (p.Arg940Ter)	HR	Pathogenic	criteria provided, multiple submitters, no conflicts
623309	NM_005144.5(HR):c.2776+1G>A	HR	Pathogenic	criteria provided, single submitter
7331	NM_005144.5(HR):c.3407T>A (p.Val1136Asp)	HR	Pathogenic	no assertion criteria provided
7340	NM_005144.5(HR):c.3034G>A (p.Asp1012Asn)	HR	Pathogenic	criteria provided, single submitter
3393319	NM_005144.5(HR):c.3199del (p.Arg1067fs)	HR	Likely pathogenic	criteria provided, single submitter
3777057	NM_005144.5(HR):c.3428_3429del (p.Pro1143fs)	HR	Likely pathogenic	criteria provided, single submitter
362479	NM_005144.5(HR):c.3250G>A (p.Ala1084Thr)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362490	NM_005144.5(HR):c.2566C>T (p.Arg856Trp)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362493	NM_005144.5(HR):c.2507G>T (p.Arg836Leu)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362496	NM_005144.5(HR):c.2367+14C>T	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362498	NM_005144.5(HR):c.2298G>A (p.Ala766=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362499	NM_005144.5(HR):c.2217C>T (p.Ser739=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362509	NM_005144.5(HR):c.1632C>T (p.Ser544=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362518	NM_005144.5(HR):c.1458A>G (p.Pro486=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362526	NM_005144.5(HR):c.970C>T (p.Arg324Trp)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
731608	NM_005144.5(HR):c.1527G>A (p.Gly509=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908090	NM_005144.5(HR):c.1618G>A (p.Glu540Lys)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910708	NM_005144.5(HR):c.3309C>T (p.Gly1103=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910823	NM_005144.5(HR):c.2354C>T (p.Pro785Leu)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910873	NM_005144.5(HR):c.1772A>G (p.Glu591Gly)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911002	NM_005144.5(HR):c.1077C>T (p.Ser359=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911929	NM_005144.5(HR):c.3228G>A (p.Gly1076=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912098	NM_005144.5(HR):c.1662C>T (p.Leu554=)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912233	NM_005144.5(HR):c.974G>A (p.Gly325Asp)	HR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700712	NM_005144.5(HR):c.212A>T (p.Asp71Val)	HR	Uncertain significance	criteria provided, single submitter
1901618	NM_005144.5(HR):c.1946C>T (p.Thr649Met)	HR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367073	NM_005144.5(HR):c.3322A>C (p.Thr1108Pro)	HR	Uncertain significance	criteria provided, single submitter
362454	NM_005144.5(HR):c.*1262G>C	HR	Uncertain significance	criteria provided, single submitter
362456	NM_005144.5(HR):c.*1150C>T	HR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HR	Strong	Autosomal recessive	alopecia universalis congenita	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HR	Orphanet:444	Marie Unna hereditary hypotrichosis
HR	Orphanet:701	Alopecia universalis
HR	Orphanet:86819	Atrichia with papular lesions

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HR	HGNC:5172	ENSG00000168453	O43593	Lysine-specific demethylase hairless	gencc,clinvar
HRURF	HGNC:55085	ENSG00000288677	P0DUH7	Protein HRURF	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HR	Lysine-specific demethylase hairless	Histone demethylase that specifically demethylates both mono- and dimethylated ‘Lys-9’ of histone H3.
HRURF	Protein HRURF	May function as an inhibitory translational control element that can negatively regulate protein translation of HR gene.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HR	Enzyme (other)	yes	1.14.11.65	JmjC_dom, LSDs-like
HRURF	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	1

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HR	235	broad	marker	skin of abdomen, skin of leg, zone of skin
HRURF

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HR	559
HRURF	0

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HRURF	P0DUH7	75.96
HR	O43593	55.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of translation	1	109.4×	0.018	HRURF
regulation of transcription by RNA polymerase II	1	5.8×	0.164	HR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HR	0	0
HRURF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HR	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HR
E	Difficult family or no structure, no drug	1	HRURF

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HR	0	—
HRURF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.