Partial androgen insensitivity syndrome

Summary

Partial androgen insensitivity syndrome (MONDO:0010720) is a disease caused by AR (GenCC Strong), with 3 cohort genes and 1 clinical trial. Top therapeutic interventions include sodium chloride.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: AR (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 52
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000151	Aplasia of the uterus	Very frequent (80-99%)
HP:0003251	Male infertility	Very frequent (80-99%)
HP:0010463	Aplasia of the ovary	Very frequent (80-99%)
HP:0011969	Elevated circulating luteinizing hormone level	Very frequent (80-99%)
HP:0030088	Increased serum testosterone level	Very frequent (80-99%)
HP:0031102	Increased antimullerian hormone level	Very frequent (80-99%)
HP:0040307	Male sexual dysfunction	Very frequent (80-99%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0008689	Bilateral cryptorchidism	Frequent (30-79%)
HP:0025132	Abnormal circulating estrogen level	Frequent (30-79%)
HP:0000027	Azoospermia	Occasional (5-29%)
HP:0000048	Bifid scrotum	Occasional (5-29%)
HP:0000051	Perineal hypospadias	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000786	Primary amenorrhea	Occasional (5-29%)
HP:0001620	Abnormally high-pitched voice	Occasional (5-29%)
HP:0008189	Insulin insensitivity	Occasional (5-29%)
HP:0008665	Clitoral hypertrophy	Occasional (5-29%)
HP:0009888	Abnormality of secondary sexual hair	Occasional (5-29%)
HP:0025134	Increased serum estradiol	Occasional (5-29%)
HP:0025486	Fused labia majora	Occasional (5-29%)
HP:0040314	Blind vagina	Occasional (5-29%)
HP:0100728	Germ cell neoplasia	Occasional (5-29%)
HP:0100779	Urogenital sinus anomaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	partial androgen insensitivity syndrome
Mondo ID	MONDO:0010720
MeSH	C538435
OMIM	307300, 312100, 312300
Orphanet	90797
DOID	DOID:0080776
ICD-10-CM	E34.52
NCIT	C120192
SNOMED CT	122811000119101
UMLS	C0268301
MedGen	82785
GARD	0005692
NORD	771
Is cancer (heuristic)	no

Also known as: androgen insensitivity syndrome, partial · androgen insensitivity, partial · androgen insensitivity, partial, with or without breast cancer · androgen insensitivity, partial, with or without breast cancer, X-linked recessive · androgen resistance syndrome, partial · familial incomplete Male pseudohermaphroditism, type 1 · incomplete male pseudohermaphroditism · PAIS · pais · partial androgen resistance syndrome · pseudohermaphroditism, incomplete male, type I · Reifenstein syndrome · Reifenstein syndrome, partial · type I familial incomplete male pseudohermaphroditism

Data availability: 52 ClinVar variants · 2 GenCC gene-disease records · 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 › partial androgen insensitivity syndrome

Related subtypes (1): complete 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

52 retrieved; paginated sample, class counts are floors:

17 pathogenic, 9 uncertain significance, 6 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 4 likely pathogenic, 3 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2572770	NM_000044.6(AR):c.2270A>G (p.Asn757Ser)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279684	NM_000044.6(AR):c.1847G>A (p.Arg616His)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
280062	NM_000044.6(AR):c.2314A>C (p.Asn772His)	AR	Pathogenic	criteria provided, single submitter
3382976	NM_000044.6(AR):c.154_220del (p.Ala52fs)	AR	Pathogenic	criteria provided, single submitter
3598420	NM_000044.6(AR):c.610G>T (p.Glu204Ter)	AR	Pathogenic	criteria provided, single submitter
448902	NM_000044.6(AR):c.1768+2T>C	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492801	NM_000044.6(AR):c.2612C>T (p.Ala871Val)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
658124	NM_000044.6(AR):c.2528T>C (p.Ile843Thr)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9806	NM_000044.6(AR):c.2599G>A (p.Val867Met)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9810	NM_000044.6(AR):c.2291A>G (p.Tyr764Cys)	AR	Pathogenic	no assertion criteria provided
9813	NM_000044.6(AR):c.1789G>A (p.Ala597Thr)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9820	NM_000044.6(AR):c.1823G>A (p.Arg608Gln)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9822	NM_000044.6(AR):c.2599G>T (p.Val867Leu)	AR	Pathogenic	no assertion criteria provided
9823	NM_000044.6(AR):c.2567G>A (p.Arg856His)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9829	NM_000044.6(AR):c.2522G>A (p.Arg841His)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9830	NM_000044.6(AR):c.2521C>T (p.Arg841Cys)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9841	NM_000044.6(AR):c.4G>A (p.Glu2Lys)	AR	Pathogenic	no assertion criteria provided
9844	NM_000044.6(AR):c.1769-11T>A	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9845	NM_000044.6(AR):c.521T>G (p.Leu174Ter)	AR	Pathogenic	no assertion criteria provided
9847	NM_000044.6(AR):c.2423T>C (p.Met808Thr)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9851	NM_000044.6(AR):c.2449+5G>T	AR	Pathogenic	no assertion criteria provided
9857	NM_000044.6(AR):c.2231G>T (p.Gly744Val)	AR	Pathogenic	criteria provided, single submitter
9860	NM_000044.6(AR):c.2222C>G (p.Ser741Cys)	AR	Pathogenic	no assertion criteria provided
1699192	NM_000044.6(AR):c.2056G>C (p.Val686Leu)	AR	Likely pathogenic	criteria provided, single submitter
2507021	NM_000044.6(AR):c.2317G>A (p.Glu773Lys)	AR	Likely pathogenic	criteria provided, single submitter
3362262	NM_000044.6(AR):c.2612C>G (p.Ala871Gly)	AR	Likely pathogenic	criteria provided, single submitter
4081595	NM_000044.6(AR):c.2329C>G (p.His777Asp)	AR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1488550	NM_000044.6(AR):c.7G>A (p.Val3Met)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216890	NM_000044.6(AR):c.1174C>T (p.Pro392Ser)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402390	NM_000044.6(AR):c.173A>T (p.Gln58Leu)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 12 · 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
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

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
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	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.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	128.6×	0.023
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

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
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

3 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)	3
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
germinal epithelium of ovary	1
tibia	1
ventricular zone	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
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AR	7,400
GLI2	3,112
AREG	2,745

Intra-cohort edges

A	B	Sources
AR	GLI2	biogrid_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AR	P10275	95
AREG	P15514	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 3 evidence-associated genes (3 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 3 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	951.7×	0.024	AREG
RUNX2 regulates chondrocyte maturation	1	761.3×	0.024	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	543.8×	0.024	GLI2
Inhibition of Signaling by Overexpressed EGFR	1	423.0×	0.024	AREG
Signaling by EGFR in Cancer	1	380.7×	0.024	AREG
EGFR interacts with phospholipase C-gamma	1	380.7×	0.024	AREG
NFE2L2 regulating tumorigenic genes	1	317.2×	0.024	AREG
RUNX2 regulates bone development	1	271.9×	0.024	AR
GRB2 events in EGFR signaling	1	253.8×	0.024	AREG
SHC1 events in EGFR signaling	1	237.9×	0.024	AREG
Cellular responses to stress	2	24.6×	0.024	AR, AREG
Cellular responses to stimuli	2	21.0×	0.024	AR, AREG
GAB1 signalosome	1	211.5×	0.025	AREG
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	181.3×	0.026	AREG
RUNX2 regulates osteoblast differentiation	1	152.3×	0.026	AR
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	152.3×	0.026	AREG
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	146.4×	0.026	AREG
PI3K/AKT Signaling in Cancer	1	122.8×	0.026	AREG
EGFR downregulation	1	115.3×	0.026	AREG
SUMOylation of intracellular receptors	1	112.0×	0.026	AR
Cargo concentration in the ER	1	112.0×	0.026	AREG
Nuclear events mediated by NFE2L2	1	112.0×	0.026	AREG
Signaling by EGFR	1	108.8×	0.026	AREG
RHO GTPases activate PKNs	1	105.7×	0.026	AR
Post-translational protein modification	2	12.8×	0.026	AR, AREG
Negative regulation of the PI3K/AKT network	1	92.8×	0.028	AREG
Transcriptional regulation by RUNX2	1	84.6×	0.030	AR
Degradation of GLI2 by the proteasome	1	74.6×	0.032	GLI2
Nuclear Receptor transcription pathway	1	66.8×	0.034	AR
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	64.5×	0.034	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 3 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	660.9×	3e-04	AR, AREG
male somatic sex determination	1	5617.3×	0.004	AR
prostate induction	1	5617.3×	0.004	AR
regulation of developmental growth	1	2808.7×	0.004	AR
lateral sprouting involved in mammary gland duct morphogenesis	1	2808.7×	0.004	AR
ventral midline development	1	1872.4×	0.004	GLI2
floor plate formation	1	1872.4×	0.004	GLI2
spinal cord ventral commissure morphogenesis	1	1872.4×	0.004	GLI2
positive regulation of integrin biosynthetic process	1	1872.4×	0.004	AR
dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis	1	1872.4×	0.004	AREG
tertiary branching involved in mammary gland duct morphogenesis	1	1872.4×	0.004	AR
positive regulation of epithelial cell proliferation involved in prostate gland development	1	1872.4×	0.004	AR
hindgut morphogenesis	1	1404.3×	0.004	GLI2
tube development	1	1404.3×	0.004	GLI2
morphogenesis of an epithelial fold	1	1404.3×	0.004	AR
cell-cell signaling	2	46.4×	0.004	AR, AREG
animal organ formation	1	1123.5×	0.005	AR
male genitalia morphogenesis	1	1123.5×	0.005	AR
epithelial cell differentiation involved in prostate gland development	1	1123.5×	0.005	AR
cerebellar cortex morphogenesis	1	936.2×	0.005	GLI2
mammary gland branching involved in thelarche	1	936.2×	0.005	AREG
epithelial cell proliferation involved in mammary gland duct elongation	1	936.2×	0.005	AREG
cellular response to testosterone stimulus	1	802.5×	0.005	AR
spinal cord dorsal/ventral patterning	1	702.2×	0.006	GLI2
prostate gland growth	1	702.2×	0.006	AR
ventral spinal cord development	1	624.1×	0.006	GLI2
prostate gland epithelium morphogenesis	1	624.1×	0.006	AR
epidermal cell differentiation	1	561.7×	0.006	GLI2
ERBB2-EGFR signaling pathway	1	561.7×	0.006	AREG
positive regulation of T cell differentiation in thymus	1	510.7×	0.007	GLI2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
GLI2	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
GLI2	6	Binding:6
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: 3; 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	2	AREG, GLI2

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)
AREG	1	—
GLI2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03171818	PHASE2	UNKNOWN	Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1