rs1386577803

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000044.6(AR):c.2495G>A(p.Arg832Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,267 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R832G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 10.0

Publications

3 publications found

Variant links:

Genes affected

AR (HGNC:644): (androgen receptor) 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]

AR Gene-Disease associations (from GenCC):

androgen insensitivity syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Kennedy disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
partial androgen insensitivity syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
complete androgen insensitivity syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

AR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000044.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-67722871-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1699233.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant X-67722872-G-A is Pathogenic according to our data. Variant chrX-67722872-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 458366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.2495G>A	p.Arg832Gln	missense_variant	Exon 7 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3 link	c.899G>A	p.Arg300Gln	missense_variant	Exon 8 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 link	c.2495G>A	p.Arg832Gln	missense_variant	Exon 7 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes

AF:

0.00000899

AC:

AN:

111267

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000379

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000899

AC:

AN:

111267

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33489

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30562

American (AMR)

AF:

0.00

AC:

AN:

10501

Ashkenazi Jewish (ASJ)

AF:

0.000379

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3506

South Asian (SAS)

AF:

0.00

AC:

AN:

2626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5991

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53026

Other (OTH)

AF:

0.00

AC:

AN:

1495

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Dec 18, 2024

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the AR gene demonstrated a sequence change, c.2495G>A, in exon 7 that results in an amino acid change, p.Arg832Gln. This sequence change has not been described in population databases such as ExAC and gnomAD (version 2). The p.Arg832Gln change affects a highly conserved amino acid residue located in a domain of the AR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg832Gln substitution. The c.2495G>A sequence change has previously been described in multiple individuals with complete androgen insensitivity (PMID: 10458483, 10834333, 2082179, 26778393). The p.Arg832Gln amino acid change occurs in a region of the AR gene where other missense sequence changes have been described in individuals with AR-related disorders (PMID: 7633398, 29051026). Functional studies have shown that this sequence change affects AR protein function (PMID: 2082179). These collective evidences indicate that this sequence change is pathogenic.

Mar 26, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate absent ligand binding activity and absence of reporter gene stimulation (PMID: 2082179); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37493574, 31277073, 20364341, 20150575, 10834333, 10458483, 26778393, 2082179, 32784047)

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 26, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Androgen resistance syndrome

Pathogenic:2

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with androgen insensitivity (MIM#300068), androgen insensitivity, partial, with or without breast cancer (MIM#312300), hypospadias 1, X-linked (MIM#300633), or spinal and bulbar muscular atrophy of Kennedy (MIM#313200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ligand binding domain of the nuclear receptor androgen receptor (NCBI conserved domains). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in hemizygous individuals with complete androgen insensitivity syndrome or aplasia of the uterus (ClinVar, DECIPHER, PMID: 30815925, PMID: 26778393, PMID: 2082179). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Genital fibroblasts from an affected individual were shown to abolish ligand binding ability (PMID: 2082179). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Androgen resistance syndrome;C1839259:Kennedy disease

Pathogenic:1

Sep 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 2082179, 7633398, 10458483). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. ClinVar contains an entry for this variant (Variation ID: 458366). This variant is also known as p.Arg830Gln and p.Arg831Gln. This missense change has been observed in individuals with androgen receptor insensitivity (PMID: 2082179, 10458483, 10834333, 20150575, 26778393). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 832 of the AR protein (p.Arg832Gln).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.75

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.0

.;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.91

ClinPred

1.0

GERP RS

5.2

Varity_R

0.99

gMVP

0.93

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over