Complete androgen insensitivity syndrome

Summary

Complete androgen insensitivity syndrome (MONDO:0021023) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide)
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.83	Worldwide	Not yet validated
Annual incidence	1-9 / 100 000	3	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0030088	Increased serum testosterone level	Very frequent (80-99%)
HP:0040314	Blind vagina	Very frequent (80-99%)
HP:0000008	Abnormal morphology of female internal genitalia	Very frequent (80-99%)
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0000151	Aplasia of the uterus	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0003251	Male infertility	Very frequent (80-99%)
HP:0008655	Aplasia/Hypoplasia of the fallopian tube	Very frequent (80-99%)
HP:0008689	Bilateral cryptorchidism	Very frequent (80-99%)
HP:0008730	Female external genitalia in individual with 46,XY karyotype	Very frequent (80-99%)
HP:0011969	Elevated circulating luteinizing hormone level	Very frequent (80-99%)
HP:0012888	Abnormality of the uterine cervix	Very frequent (80-99%)
HP:0025134	Increased serum estradiol	Very frequent (80-99%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0002215	Sparse axillary hair	Frequent (30-79%)
HP:0002221	Absent axillary hair	Frequent (30-79%)
HP:0002225	Sparse pubic hair	Frequent (30-79%)
HP:0002555	Absent pubic hair	Frequent (30-79%)
HP:0031102	Increased antimullerian hormone level	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0010788	Testicular neoplasm	Occasional (5-29%)
HP:0001061	Acne	Very rare (<1-4%)
HP:0030346	Abnormal circulating follicle-stimulating hormone level	Very rare (<1-4%)
HP:0100728	Germ cell neoplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	complete androgen insensitivity syndrome
Mondo ID	MONDO:0021023
Orphanet	99429
DOID	DOID:0080775
ICD-10-CM	E34.51
NCIT	C120191
SNOMED CT	368851000119102
UMLS	C0936016
MedGen	183188
GARD	0010597
Is cancer (heuristic)	no

Also known as: androgen insensitivity syndrome, complete · CAIS · complete androgen resistance syndrome

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › androgen insensitivity syndrome › complete androgen insensitivity syndrome

Related subtypes (1): partial androgen insensitivity syndrome

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3340490	NM_000044.6(AR):c.1095C>A (p.Tyr365Ter)	AR	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 4 · 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
AR	Definitive	X-linked	androgen insensitivity syndrome	13
AREG	Definitive	X-linked	androgen insensitivity syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AR	Orphanet:481	Kennedy disease
AR	Orphanet:90797	Partial androgen insensitivity syndrome
AR	Orphanet:95706	Non-syndromic posterior hypospadias
AR	Orphanet:99429	Complete androgen insensitivity syndrome

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
AR	HGNC:644	ENSG00000169083	P10275	Androgen receptor	gencc,clinvar
AREG	HGNC:651	ENSG00000109321	P15514	Amphiregulin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AR	Androgen receptor	Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
AREG	Amphiregulin	Ligand of the EGF receptor/EGFR.

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
Nuclear receptor	1	192.9×	0.010
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AR	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Andrgn_rcpt, Znf_hrmn_rcpt
AREG	Other/Unknown	no		EGF

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nipple	1
seminal vesicle	1
urethra	1
endometrium epithelium	1
mucosa of urinary bladder	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AR	250	ubiquitous	marker	seminal vesicle, urethra, nipple
AREG	216	ubiquitous	marker	mucosa of urinary bladder, endometrium epithelium, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AR	7,400
AREG	2,745

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AR	P10275	95
AREG	P15514	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 63. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by Overexpressed Wild-Type EGFR in Cancer	1	1427.5×	0.016	AREG
Inhibition of Signaling by Overexpressed EGFR	1	634.4×	0.016	AREG
Signaling by EGFR in Cancer	1	571.0×	0.016	AREG
EGFR interacts with phospholipase C-gamma	1	571.0×	0.016	AREG
NFE2L2 regulating tumorigenic genes	1	475.8×	0.016	AREG
RUNX2 regulates bone development	1	407.9×	0.016	AR
GRB2 events in EGFR signaling	1	380.7×	0.016	AREG
SHC1 events in EGFR signaling	1	356.9×	0.016	AREG
Cellular responses to stress	2	36.8×	0.016	AR, AREG
Cellular responses to stimuli	2	31.5×	0.016	AR, AREG
Post-translational protein modification	2	19.2×	0.016	AR, AREG
GAB1 signalosome	1	317.2×	0.017	AREG
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.017	AREG
RUNX2 regulates osteoblast differentiation	1	228.4×	0.017	AR
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.017	AREG
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	219.6×	0.017	AREG
PI3K/AKT Signaling in Cancer	1	184.2×	0.017	AREG
EGFR downregulation	1	173.0×	0.017	AREG
SUMOylation of intracellular receptors	1	167.9×	0.017	AR
Cargo concentration in the ER	1	167.9×	0.017	AREG
Nuclear events mediated by NFE2L2	1	167.9×	0.017	AREG
Signaling by EGFR	1	163.1×	0.017	AREG
RHO GTPases activate PKNs	1	158.6×	0.017	AR
Metabolism of proteins	2	12.4×	0.017	AR, AREG
Negative regulation of the PI3K/AKT network	1	139.3×	0.018	AREG
Transcriptional regulation by RUNX2	1	126.9×	0.019	AR
Nuclear Receptor transcription pathway	1	100.2×	0.022	AR
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.022	AR
Signal Transduction	2	10.2×	0.022	AR, AREG
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.023	AR

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
mammary gland alveolus development	2	991.3×	6e-05	AR, AREG
male somatic sex determination	1	8426.0×	0.002	AR
prostate induction	1	8426.0×	0.002	AR
regulation of developmental growth	1	4213.0×	0.002	AR
lateral sprouting involved in mammary gland duct morphogenesis	1	4213.0×	0.002	AR
positive regulation of integrin biosynthetic process	1	2808.7×	0.002	AR
dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis	1	2808.7×	0.002	AREG
tertiary branching involved in mammary gland duct morphogenesis	1	2808.7×	0.002	AR
positive regulation of epithelial cell proliferation involved in prostate gland development	1	2808.7×	0.002	AR
cell-cell signaling	2	69.6×	0.002	AR, AREG
morphogenesis of an epithelial fold	1	2106.5×	0.003	AR
animal organ formation	1	1685.2×	0.003	AR
male genitalia morphogenesis	1	1685.2×	0.003	AR
epithelial cell differentiation involved in prostate gland development	1	1685.2×	0.003	AR
mammary gland branching involved in thelarche	1	1404.3×	0.003	AREG
epithelial cell proliferation involved in mammary gland duct elongation	1	1404.3×	0.003	AREG
cellular response to testosterone stimulus	1	1203.7×	0.003	AR
positive regulation of cell population proliferation	2	33.6×	0.003	AR, AREG
prostate gland growth	1	1053.2×	0.003	AR
prostate gland epithelium morphogenesis	1	936.2×	0.004	AR
ERBB2-EGFR signaling pathway	1	842.6×	0.004	AREG
positive regulation of intracellular estrogen receptor signaling pathway	1	601.9×	0.004	AR
Leydig cell differentiation	1	601.9×	0.004	AR
positive regulation of insulin-like growth factor receptor signaling pathway	1	601.9×	0.004	AR
membraneless organelle assembly	1	561.7×	0.004	AR
regulation of systemic arterial blood pressure	1	526.6×	0.004	AR
cellular response to steroid hormone stimulus	1	526.6×	0.004	AR
positive regulation of keratinocyte proliferation	1	495.6×	0.004	AREG
intracellular receptor signaling pathway	1	495.6×	0.004	AR
epithelial cell morphogenesis	1	468.1×	0.004	AR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AR	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AR	116	4
AREG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR
MOMETASONE FUROATE	4	AR
TESTOSTERONE PROPIONATE	4	AR
ESTRADIOL ACETATE	4	AR
OXANDROLONE	4	AR
BECLOMETHASONE DIPROPIONATE	4	AR
DIFLORASONE DIACETATE	4	AR
ETHYNODIOL DIACETATE	4	AR
HALCINONIDE	4	AR
DYDROGESTERONE	4	AR
FLUMETHASONE PIVALATE	4	AR
HALOBETASOL PROPIONATE	4	AR
ESTRADIOL CYPIONATE	4	AR
CLOCORTOLONE PIVALATE	4	AR
FLURANDRENOLIDE	4	AR
MEGESTROL ACETATE	4	AR
NORETHINDRONE ACETATE	4	AR
SERTACONAZOLE	4	AR
PYRVINIUM	4	AR
PRASUGREL	4	AR
OXICONAZOLE	4	AR
NILUTAMIDE	4	AR
MIFEPRISTONE	4	AR
PREDNISOLONE	4	AR
ESTRADIOL	4	AR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AR	2,100	Binding:1727, Functional:339, ADMET:33, Unclassified:1
AREG	1	Functional:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
AR	2,100

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR
MOMETASONE FUROATE	4	AR
TESTOSTERONE PROPIONATE	4	AR
ESTRADIOL ACETATE	4	AR
OXANDROLONE	4	AR
BECLOMETHASONE DIPROPIONATE	4	AR
DIFLORASONE DIACETATE	4	AR
ETHYNODIOL DIACETATE	4	AR
HALCINONIDE	4	AR
DYDROGESTERONE	4	AR
FLUMETHASONE PIVALATE	4	AR
HALOBETASOL PROPIONATE	4	AR
ESTRADIOL CYPIONATE	4	AR
CLOCORTOLONE PIVALATE	4	AR
FLURANDRENOLIDE	4	AR
MEGESTROL ACETATE	4	AR
NORETHINDRONE ACETATE	4	AR
SERTACONAZOLE	4	AR
PYRVINIUM	4	AR
PRASUGREL	4	AR
OXICONAZOLE	4	AR
NILUTAMIDE	4	AR
MIFEPRISTONE	4	AR
PREDNISOLONE	4	AR
ESTRADIOL	4	AR

Druggability pyramid

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

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AREG	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.