AR

protein-coding

androgen receptor, the group of Nuclear receptor subfamily 3 group C

Gene summary

The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

Previous symbols:

DHTR
SBMA

MANE transcript

NM_000044.6

Inheritance

ClinVar variants

P:393U:235B:293

Top phenotype

Androgen insensitivity; Androgen insensitivity, partial

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chrX:67,544,021-67,730,619

External References & Databases

Ensembl (ENSG00000169083)

Transcript & Mutation Effects

hg38 • Region Span ~186.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

androgen insensitivity syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019154

Submitter: Ambry Genetics

partial androgen insensitivity syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010720

Submitter: Genomics England PanelApp

Kennedy diseaseSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: Orphanet

partial androgen insensitivity syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010720

Submitter: Orphanet

Kennedy diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: ClinGen

AR was first reported in relation to X-linked Kennedy disease in 1991 (La Spada et al., PMID: 2062380). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the Kennedy disease (OMIM:313200) entity has been split from the following disease entities: hypospadias 1, X-linked (OMIM:300633), androgen insensitivity, partial, with or without breast cancer (OMIM:312300), androgen insensitivity (OMIM:300068), and prostate cancer, susceptibility to (OMIM:176807). One variant (trinucleotide repeat expansion) that has been reported in 15 probands in 6 publications (PMIDs: 2062380, 1303195, 15659427, 25047668, 28877561, 37058074) is included in this curation. More evidence is available in the literature. The mechanism of pathogenicity is currently unknown; hypotheses with experimental support include disruption of AR's function as a transcription factor, altered interactions between AR protein and its coactivators and corepressors, and formation of nulear inclusions by peptides after proteolytic processing of AR. The gene-disease relationship is also supported by animal models, expression studies, functional alteration in patient cells, and rescue in non-human model organisms (PMIDs: 15003169, 24309898, 19279159, 15659427, 9708548, 12372280). In summary, there is definitive evidence supporting the relationship between AR and X-linked Kennedy disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on the meeting date August 8, 2023 (SOP Version 9).

Kennedy diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: Ambry Genetics

complete androgen insensitivity syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0021023

Submitter: Orphanet

Kennedy diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: Labcorp Genetics (formerly Invitae)

androgen insensitivity syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0019154

Submitter: Labcorp Genetics (formerly Invitae)

androgen insensitivity syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0019154

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

androgen insensitivity syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0019154

Submitter: PanelApp Australia

Kennedy diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: G2P

Kennedy diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010735

Submitter: PanelApp Australia

androgen insensitivity syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019154

Submitter: G2P

Clinical Genomic Database (CGD)

Androgen insensitivity; Androgen insensitivity, partialXL

Manifestation: Endocrine; Genitourinary; Neurologic; Oncologic

Intervention: Endocrine; Oncologic; Genitourinary

Rationale: Treatment with testosterone, starting at an early age may enable fertility; Surveillance for breast cancer may be beneficial

Refs: 17564966; 21057504; 20929961; 22499348

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AR variants in ClinVar

30 Conditions Cataloged

Androgen resistance syndromeTotal: 780

Kennedy diseaseTotal: 647

not providedTotal: 209

not specifiedTotal: 101

AR-related disorderTotal: 84

Inborn genetic diseasesTotal: 57

Partial androgen insensitivity syndromeTotal: 54

AR-related disordersTotal: 31

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000044.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		4 clinvar	215 clinvar	32 clinvar	252
missense	80 clinvar	129 clinvar	220 clinvar	29 clinvar	17 clinvar	475
nonsense	66 clinvar	8 clinvar	4 clinvar			78
start loss	2 clinvar	1 clinvar				3
frameshift	73 clinvar	16 clinvar	1 clinvar			90
splice donor/acceptor (+/-2bp)	8 clinvar	9 clinvar	6 clinvar			23
Total	230	163	235	244	49	921

Highest pathogenic variant AF is 0.0001445903

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000044.6	RefSeq	NP_000035.2	8	MANE Select
ENST00000374690.9	Ensembl	ENSP00000363822.3	8	MANE Select
NM_001011645.3	RefSeq	NP_001011645.1	8	Standard
NM_001348061.1	RefSeq	NP_001334990.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ar	Danio rerio	Structure: testis Quality: lacks all parts of type abnormal

Gene / Model

Organism

Observed Phenotype

Danio rerio

Structure: testis

Quality: lacks all parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oocyte meiosis - Homo sapiens (human)
Prostate cancer - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
NHR
Androgen receptor signaling pathway

Biological Process

negative regulation of transcription by RNA polymerase II
in utero embryonic development
regulation of systemic arterial blood pressure
epithelial cell morphogenesis
transcription, DNA-templated

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
RNA polymerase II general transcription initiation factor binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374690
Coding exons: 8
Length: 185997
Individuals with no LoFs: 125666
Homozygous LoFs: 17
Heterozygous LoFs: 2
Defined: 125685
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.23	286	351	0.816	0.0000250	5916
Missense (PolyPhen)		84	162.37	0.51735		2689
Synonymous	-0.838	159	146	1.09	0.0000106	1867
Loss of Function	4.25	3	26.7	0.113	0.00000190	426

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.000062	rare
Latino/Admixed American	0.00044	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.000044	rare
South Asian	0.00023	0.000065	rare
Other	0.0015	0.00033	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20812024, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:25091737}.;
Disease: DISEASE: Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10221770, ECO:0000269|PubMed:10404311, ECO:0000269|PubMed:10458483, ECO:0000269|PubMed:10571951, ECO:0000269|PubMed:10590024, ECO:0000269|PubMed:10690872, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:11744994, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1426313, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:1464650, ECO:0000269|PubMed:14756668, ECO:0000269|PubMed:1480178, ECO:0000269|PubMed:1487249, ECO:0000269|PubMed:1569163, ECO:0000269|PubMed:1609793, ECO:0000269|PubMed:16129672, ECO:0000269|PubMed:16595706, ECO:0000269|PubMed:1775137, ECO:0000269|PubMed:1999491, ECO:0000269|PubMed:2082179, ECO:0000269|PubMed:2594783, ECO:0000269|PubMed:7537149, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7633398, ECO:0000269|PubMed:7641413, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7962294, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:7981689, ECO:0000269|PubMed:7993455, ECO:0000269|PubMed:8040309, ECO:0000269|PubMed:8096390, ECO:0000269|PubMed:8103398, ECO:0000269|PubMed:8162033, ECO:0000269|PubMed:8224266, ECO:0000269|PubMed:8281140, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8339746, ECO:0000269|PubMed:8413310, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8626869, ECO:0000269|PubMed:8647313, ECO:0000269|PubMed:8683794, ECO:0000269|PubMed:8723113, ECO:0000269|PubMed:8768864, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8830623, ECO:0000269|PubMed:8918984, ECO:0000269|PubMed:8990010, ECO:0000269|PubMed:9001799, ECO:0000269|PubMed:9007482, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9106550, ECO:0000269|PubMed:9160185, ECO:0000269|PubMed:9252933, ECO:0000269|PubMed:9255042, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9328206, ECO:0000269|PubMed:9544375, ECO:0000269|PubMed:9554754, ECO:0000269|PubMed:9610419, ECO:0000269|PubMed:9627582, ECO:0000269|PubMed:9698822, ECO:0000269|PubMed:9851768, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.113, ECO:0000269|Ref.179}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269|PubMed:15851746}. Note=The disease is caused by mutations affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.; DISEASE: Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. {ECO:0000269|PubMed:10363963, ECO:0000269|PubMed:10569618, ECO:0000269|PubMed:1562539, ECO:0000269|PubMed:16129672, ECO:0000269|PubMed:17311914, ECO:0000269|PubMed:2260966, ECO:0000269|PubMed:25091737, ECO:0000269|PubMed:8187068, ECO:0000269|PubMed:8274409, ECO:0000269|PubMed:8827083}.; DISEASE: Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10470409, ECO:0000269|PubMed:10502786, ECO:0000269|PubMed:10543676, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:1303262, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1424203, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:14756668, ECO:0000269|PubMed:2010552, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7649358, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7909256, ECO:0000269|PubMed:7910529, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:8033918, ECO:0000269|PubMed:8097257, ECO:0000269|PubMed:8126121, ECO:0000269|PubMed:8205256, ECO:0000269|PubMed:8281139, ECO:0000269|PubMed:8325932, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8550758, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8823308, ECO:0000269|PubMed:8824883, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9196614, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9329414, ECO:0000269|PubMed:9543136, ECO:0000269|PubMed:9607727, ECO:0000269|PubMed:9768671, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.121}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.975

Intolerance Scores

LoFtool: 0.0125
RVIS EVS: -0.62
RVIS percentile EVS: 17.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium