SRD5A3

Summary

SRD5A3 (steroid 5 alpha-reductase 3, HGNC:25812) is a protein-coding gene on chromosome 4q12, encoding Polyprenal reductase (Q9H8P0). Plays a key role in early steps of protein N-linked glycosylation by being involved in the conversion of polyprenol into dolichol. It is a selective cancer dependency (DepMap: 13.2% of cell lines).

The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type Iq.

Source: NCBI Gene 79644 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SRD5A3-congenital disorder of glycosylation (Definitive, ClinGen)
• GWAS associations: 26
• Clinical variants (ClinVar): 205 total — 12 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 13.2% of screened cell lines
• MANE Select transcript: NM_024592

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25812
Approved symbol	SRD5A3
Name	steroid 5 alpha-reductase 3
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13352, SRD5A2L, SRD5A2L1
Ensembl gene	ENSG00000128039
Ensembl biotype	protein_coding
OMIM	611715
Entrez	79644

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000264228, ENST00000505210, ENST00000514398, ENST00000677177, ENST00000677217, ENST00000677930, ENST00000678717, ENST00000679836, ENST00000870317, ENST00000870318, ENST00000918496

RefSeq mRNA: 2 — MANE Select: NM_024592 NM_001410732, NM_024592

CCDS: CCDS3498, CCDS93533

Canonical transcript exons

ENST00000264228 — 5 exons

Exon	Start	End
ENSE00001001874	55367588	55367722
ENSE00001074537	55346242	55346557
ENSE00001074541	55369832	55373100
ENSE00003662441	55364074	55364271
ENSE00003681768	55359346	55359488

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 94.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.2250 / max 287.4450, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47691	15.3666	1806
47693	0.5773	310
47689	0.1409	33
47690	0.1402	30

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	94.57	gold quality
gall bladder	UBERON:0002110	92.06	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.73	gold quality
esophagus mucosa	UBERON:0002469	91.19	gold quality
body of pancreas	UBERON:0001150	90.13	gold quality
upper leg skin	UBERON:0004262	90.10	gold quality
gingival epithelium	UBERON:0001949	90.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.91	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.88	gold quality
epithelium of nasopharynx	UBERON:0001951	89.49	gold quality
nasopharynx	UBERON:0001728	89.48	gold quality
gingiva	UBERON:0001828	89.12	gold quality
islet of Langerhans	UBERON:0000006	88.94	gold quality
stromal cell of endometrium	CL:0002255	88.70	gold quality
eye	UBERON:0000970	88.57	gold quality
minor salivary gland	UBERON:0001830	87.88	gold quality
pancreas	UBERON:0001264	87.86	gold quality
mouth mucosa	UBERON:0003729	87.26	gold quality
left adrenal gland	UBERON:0001234	86.88	gold quality
lower esophagus mucosa	UBERON:0035834	86.67	gold quality
right adrenal gland	UBERON:0001233	86.63	gold quality
right adrenal gland cortex	UBERON:0035827	86.60	gold quality
skin of abdomen	UBERON:0001416	86.55	gold quality
skin of leg	UBERON:0001511	86.36	gold quality
spinal cord	UBERON:0002240	86.22	gold quality
left adrenal gland cortex	UBERON:0035825	86.13	gold quality
mucosa of transverse colon	UBERON:0004991	85.80	gold quality
prefrontal cortex	UBERON:0000451	85.77	gold quality
endometrium	UBERON:0001295	85.56	gold quality
esophagus squamous epithelium	UBERON:0006920	85.51	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	125.29
E-ANND-3	yes	8.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

115 targeting SRD5A3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• Findings indicate that a novel type 3 5 alpha-steroid reductase, SRD5A3, is associated with DHT production and maintenance of androgen-androgen receptor-pathway activation in prostate cancer. (PMID:17986282)
• Study of a large consanguineous Emirati family showed that loss of function mutations of the SRD5A3 gene cause a multisystemic syndrome with eye malformations, cerebellar vermis hypoplasia, and psychomotor delay. (PMID:20637498)
• Next generation sequencing identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) SRD5A3 as the disease-causing change in Kahrizi syndrome. (PMID:20700148)
• A novel syndrome is identified in families with cerebellar ataxia and congenital eye malformations due to steroid 5 alpha-reductase type 3 disorders of glycosylation. (PMID:20852264)
• Findings suggest that overexpression of 5alpha-reductase, through a higher inactivation of cortisol in the liver, could have a protective role in preserving hepatic sensitivity to insulin. (PMID:21704348)
• the spectrum of phenotypes resulting from SRD5A3 mutations and the clinical variability of SRD5A3-CDG (PMID:24433453)
• Although 4-dione is the main source of 5alpha-dihydrotestosterone in human preadipocytes, production of this steroid by 5 alpha-reductase isoenzymes (SRD5A1, 2 and 3) mediates the inhibitory effect of both 4-dione and testosterone on preadipocyte differentiation. (PMID:26855069)
• We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement (PMID:27480077)
• Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. (PMID:28253385)
• Study revealed for the first time the presence of 5alpha-reductase-R3 mRNA in human hair. (PMID:29185104)
• Findings suggest that 5alpha-reductases (5-AR) isoenzymes could be explored as a therapeutic target for urothelial bladder cancer (UBC) with 5alpha-reductase inhibitors (5-ARI). (PMID:29187470)
• Steroid 5 alpha-reductase 3 (SRD5A3) promotes tumor growth and predicts poor survival of human hepatocellular carcinoma (HCC). (PMID:33229626)
• SRD5A3-CDG: 3D structure modeling, clinical spectrum, and computer-based dysmorphic facial recognition. (PMID:33403770)
• Over-expression of SRD5A3 and its prognostic significance in breast cancer. (PMID:34465365)
• Analysis of the implication of steroid 5 alpha-reductase 3 on prognosis and immune microenvironment in Liver Hepatocellular Carcinoma. (PMID:39340288)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	srd5a3	ENSDARG00000043307
mus_musculus	Srd5a3	ENSMUSG00000029233
rattus_norvegicus	Srd5a3	ENSRNOG00000002216
drosophila_melanogaster	CG7840	FBGN0032014
caenorhabditis_elegans		WBGENE00007102

Protein

Protein identifiers

Polyprenal reductase — Q9H8P0 (reviewed: Q9H8P0)

Alternative names: 3-oxo-5-alpha-steroid 4-dehydrogenase 3, Steroid 5-alpha-reductase 2-like, Steroid 5-alpha-reductase 3

All UniProt accessions (4): Q9H8P0, A0A7I2V5I5, A0A7P0TBH6, H0Y9P9

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role in early steps of protein N-linked glycosylation by being involved in the conversion of polyprenol into dolichol. Acts as a polyprenal reductase that mediates the reduction of polyprenal into dolichal in a NADP-dependent mechanism. Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation. Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in preadipocytes (at protein level). Overexpressed in hormone-refractory prostate cancers (HRPC). Almost no or little expression in normal adult organs.

Disease relevance. Congenital disorder of glycosylation 1Q (CDG1Q) [MIM:612379] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry. Kahrizi syndrome (KHRZ) [MIM:612713] An autosomal recessive neurodevelopmental disorder characterized by intellectual disability, cataracts, coloboma, kyphosis, and coarse facial features. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the steroid 5-alpha reductase family. Polyprenal reductase subfamily.

RefSeq proteins (2): NP_001397661, NP_078868* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001104	3-oxo-5_a-steroid_4-DH_C	Domain
IPR039698	Dfg10/SRD5A3	Family

Pfam: PF02544

Enzyme classification (BRENDA):

• EC 1.3.1.22 — 3-oxo-5alpha-steroid 4-dehydrogenase (NADP+) (BRENDA: 19 organisms, 63 substrates, 409 inhibitors, 93 Km, 0 kcat entries)
• EC 1.3.1.94 — polyprenal reductase (BRENDA: 7 organisms, 9 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 1.3.1.B13 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TESTOSTERONE	—	36
NADPH	0.001–0.65	17
PROGESTERONE	0.0001–0.12	15
ANDROSTENEDIONE	0.0004–0.0263	7
CORTICOSTERONE	0.0006–0.018	5
20ALPHA-HYDROXYPROGESTERONE	0.0002–0.0005	3
17-EPITESTOSTERONE	0.0006–0.0008	2
17ALPHA-HYDROXYPROGESTERONE	0.0061–0.0088	2
20ALPHA-HYDROXYPREGN-4-EN-3-ONE	0.0009	1
3-KETO-DELTA4-ABIRATERONE	0.003	1
CORTISONE	0.14	1
DIHYDROTESTOSTERONE	0.0014	1

Catalyzed reactions (Rhea), 4 shown:

• androst-4-ene-3,17-dione + NADPH + H(+) = 5alpha-androstan-3,17-dione + NADP(+) (RHEA:50816)
• 17beta-hydroxy-5alpha-androstan-3-one + NADP(+) = testosterone + NADPH + H(+) (RHEA:50820)
• a 3-oxo-5alpha-steroid + NADP(+) = a 3-oxo-Delta(4)-steroid + NADPH + H(+) (RHEA:54384)
• a di-trans,poly-cis-dolichal + NADP(+) = a di-trans,poly-cis-polyprenal + NADPH + H(+) (RHEA:80727)

UniProt features (24 total): sequence variant 9, topological domain 7, transmembrane region 6, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H8P0-F1	89.07	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
296	loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-193048	Androgen biosynthesis
R-HSA-446199	Synthesis of dolichyl-phosphate
R-HSA-4755579	Defective SRD5A3 causes SRD5A3-CDG, KHRZ
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196071	Metabolism of steroid hormones
R-HSA-3781865	Diseases of glycosylation
R-HSA-392499	Metabolism of proteins
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-446219	Synthesis of substrates in N-glycan biosythesis
R-HSA-556833	Metabolism of lipids
R-HSA-5609975	Diseases associated with glycosylation precursor biosynthesis
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 312 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_ANDROGEN_BIOSYNTHETIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_HORMONE_BIOSYNTHETIC_PROCESS

GO Biological Process (9): dolichol-linked oligosaccharide biosynthetic process (GO:0006488), androgen biosynthetic process (GO:0006702), polyprenol catabolic process (GO:0016095), dolichyl monophosphate biosynthetic process (GO:0043048), obsolete protein glycosylation (GO:0006486), dolichyl diphosphate biosynthetic process (GO:0006489), lipid metabolic process (GO:0006629), obsolete dolichol metabolic process (GO:0019348), obsolete dolichol biosynthetic process (GO:0019408)

GO Molecular Function (7): 3-oxo-5-alpha-steroid 4-dehydrogenase activity (GO:0003865), oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor (GO:0016628), 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity (GO:0047751), polyprenol reductase activity (GO:0102389), polyprenal reductase activity (GO:0160198), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Metabolism of steroid hormones	1
Synthesis of substrates in N-glycan biosythesis	1
Diseases associated with glycosylation precursor biosynthesis	1
Metabolism of steroids	1
Diseases of metabolism	1
Asparagine N-linked glycosylation	1
Post-translational protein modification	1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1
Metabolism	1
Diseases of glycosylation	1
Disease	1
Metabolism of proteins	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phospholipid biosynthetic process	2
oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor	2
cellular anatomical structure	2
protein N-linked glycosylation	1
carbohydrate derivative biosynthetic process	1
androgen metabolic process	1
hormone biosynthetic process	1
steroid hormone biosynthetic process	1
isoprenoid catabolic process	1
polyprenol metabolic process	1
alcohol catabolic process	1
dolichol-linked oligosaccharide biosynthetic process	1
primary metabolic process	1
steroid dehydrogenase activity, acting on the CH-CH group of donors	1
oxidoreductase activity, acting on the CH-CH group of donors	1
3-oxo-5-alpha-steroid 4-dehydrogenase activity	1
enone reductase activity	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRD5A3	SRD5A1	P18405	967
SRD5A3	TECRL	Q5HYJ1	920
SRD5A3	PMM2	O15305	861
SRD5A3	TECR	Q9NZ01	859
SRD5A3	MPI	P34949	859
SRD5A3	DOLK	Q9UPQ8	795
SRD5A3	DHDDS	Q86SQ9	735
SRD5A3	DOLPP1	Q86YN1	725
SRD5A3	ALG6	Q9Y672	723
SRD5A3	DPAGT1	Q9H3H5	669
SRD5A3	DPM1	O60762	658
SRD5A3	AKR1C3	P42330	657
SRD5A3	ALG8	Q9BVK2	657
SRD5A3	NUS1	Q96E22	646
SRD5A3	HSD3B2	P26439	640

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SRD5A3	ADK	psi-mi:“MI:0915”(physical association)	0.370
SRD5A3	NUDT15	psi-mi:“MI:0915”(physical association)	0.370
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): SRD5A3 (Affinity Capture-RNA), SRD5A3 (Affinity Capture-MS), SRD5A3 (Affinity Capture-MS), SRD5A3 (Affinity Capture-RNA), SRD5A3 (Phenotypic Suppression), SRD5A3 (Two-hybrid), SRD5A3 (Two-hybrid)

ESM2 similar proteins: A2XWN6, A2XX73, A5PJS2, B8B6G5, C7T2J9, D2HBV9, I1HTF7, O08984, O12947, O18765, O60725, O75908, O76062, O77759, O88908, P18405, P24008, P31213, P31214, Q0P4J9, Q28891, Q28892, Q3U9G9, Q4KLV1, Q4R8A8, Q4V7R2, Q5BJF2, Q5RIU9, Q5RJM1, Q68FF9, Q71KT5, Q7F0Q2, Q7TQM4, Q7XSR9, Q7XUH5, Q8AVI9, Q8WMV1, Q8WUD6, Q99N99, Q9CAH5

Diamond homologs: A2XWN6, A5PJS2, A8X8R3, B8B6G5, C7T2J9, D2HBV9, I1HTF7, O18765, O94511, P18405, P24008, P31213, P31214, Q17428, Q28891, Q28892, Q2QDF6, Q38944, Q55C17, Q5K2N1, Q5RJM1, Q68FF9, Q7F0Q2, Q7XUH5, Q99N99, Q9CAH5, Q9H8P0, Q9N5Y2, Q9SI62, Q9UT20, Q9WUP4, P40526, Q0P4J9, Q5RIU9, Q8AVI9, Q3SZ89, Q9VLP9, Q9M2U2, Q5HYJ1, Q3ZCD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

205 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	6
Uncertain significance	93
Likely benign	55
Benign	20

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1362615	NM_024592.5(SRD5A3):c.279C>A (p.Cys93Ter)	Pathogenic
1456803	NC_000004.11:g.(?56225493)(56225675_?)del	Pathogenic
18404	NM_024592.5(SRD5A3):c.286_288delinsTGAGTAAGGC (p.Gln96Ter)	Pathogenic
18405	NM_024592.5(SRD5A3):c.320G>A (p.Trp107Ter)	Pathogenic
18406	NM_024592.5(SRD5A3):c.424C>T (p.Arg142Ter)	Pathogenic
18407	NM_024592.5(SRD5A3):c.489C>A (p.Tyr163Ter)	Pathogenic
18408	NM_024592.5(SRD5A3):c.29C>A (p.Ser10Ter)	Pathogenic
2446387	NM_024592.5(SRD5A3):c.50_60del (p.Ala17fs)	Pathogenic
30929	NM_024592.5(SRD5A3):c.204dup (p.Phe69fs)	Pathogenic
423433	NM_024592.5(SRD5A3):c.66del (p.Thr23fs)	Pathogenic
498853	NM_024592.5(SRD5A3):c.364G>T (p.Gly122Ter)	Pathogenic
96125	NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)	Pathogenic
1180838	NM_024592.5(SRD5A3):c.698-1G>A	Likely pathogenic
1196871	NM_024592.5(SRD5A3):c.617G>T (p.Gly206Val)	Likely pathogenic
1343405	NM_024592.4:c.(221+1_222-1)_(697+1_698-1)dup	Likely pathogenic
2571874	NM_024592.5(SRD5A3):c.176dup (p.Pro60fs)	Likely pathogenic
2630646	NM_024592.5(SRD5A3):c.445_446dup (p.Val150fs)	Likely pathogenic
690313	NM_024592.5(SRD5A3):c.921G>C (p.Pro307=)	Likely pathogenic

SpliceAI

1057 predictions. Top by Δscore:

Variant	Effect	Δscore
4:55366984:GCAT:G	donor_gain	1.0000
4:55366987:T:TG	donor_gain	1.0000
4:55346553:AAGAG:A	donor_loss	0.9900
4:55346555:G:GT	donor_gain	0.9900
4:55346555:GAG:G	donor_gain	0.9900
4:55346556:AG:A	donor_loss	0.9900
4:55346557:GG:G	donor_loss	0.9900
4:55346558:GTAA:G	donor_loss	0.9900
4:55346559:T:A	donor_loss	0.9900
4:55359345:GAT:G	acceptor_gain	0.9900
4:55359487:GG:G	donor_gain	0.9900
4:55359488:GG:G	donor_gain	0.9900
4:55366983:GGCAT:G	donor_gain	0.9900
4:55349785:G:GT	donor_gain	0.9800
4:55359341:TGCA:T	acceptor_loss	0.9800
4:55359342:GCA:G	acceptor_loss	0.9800
4:55359344:A:AG	acceptor_gain	0.9800
4:55359344:A:C	acceptor_loss	0.9800
4:55359345:G:GG	acceptor_gain	0.9800
4:55363843:G:GT	donor_gain	0.9800
4:55363852:T:G	donor_gain	0.9800
4:55363852:T:TG	donor_gain	0.9800
4:55363889:AACAC:A	donor_gain	0.9800
4:55363890:ACACA:A	donor_gain	0.9800
4:55367586:A:AG	acceptor_gain	0.9800
4:55367587:G:GG	acceptor_gain	0.9800
4:55349852:T:G	donor_gain	0.9700
4:55363826:G:GT	donor_gain	0.9700
4:55359345:GATA:G	acceptor_gain	0.9600
4:55359345:GATAT:G	acceptor_gain	0.9600

AlphaMissense

2070 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:55369876:T:C	F248L	0.989
4:55369878:T:A	F248L	0.989
4:55369878:T:G	F248L	0.989
4:55370064:G:C	R310S	0.982
4:55370064:G:T	R310S	0.982
4:55370041:T:C	F303L	0.980
4:55370043:T:A	F303L	0.980
4:55370043:T:G	F303L	0.980
4:55364166:T:C	F153L	0.973
4:55364168:C:A	F153L	0.973
4:55364168:C:G	F153L	0.973
4:55369963:T:A	W277R	0.971
4:55369963:T:C	W277R	0.971
4:55367709:G:C	R228S	0.970
4:55367709:G:T	R228S	0.970
4:55370063:G:C	R310T	0.969
4:55370063:G:T	R310M	0.968
4:55364127:A:C	S140R	0.967
4:55364129:C:A	S140R	0.967
4:55364129:C:G	S140R	0.967
4:55369895:C:A	P254H	0.967
4:55369876:T:A	F248I	0.962
4:55369886:T:A	V251D	0.962
4:55369873:T:A	W247R	0.960
4:55369873:T:C	W247R	0.960
4:55364137:G:C	R143T	0.959
4:55367708:G:C	R228T	0.955
4:55359350:T:C	F76L	0.954
4:55359352:T:A	F76L	0.954
4:55359352:T:G	F76L	0.954

dbSNP variants (sampled 300 via entrez): RS1000127025 (4:55356561 T>TA), RS10002545 (4:55355577 G>A), RS1000257667 (4:55357443 G>A,T), RS1000291769 (4:55368344 G>A,T), RS1000477414 (4:55365802 G>A), RS1000613660 (4:55353269 T>C), RS1000977918 (4:55363322 C>T), RS1000995796 (4:55359201 T>C), RS1001079338 (4:55353937 C>T), RS1001130188 (4:55357985 C>T), RS1001251882 (4:55356866 G>C), RS10013154 (4:55353645 G>A), RS1001325402 (4:55363170 A>G), RS1001385878 (4:55362359 C>T), RS1001656078 (4:55356153 C>T)

Disease associations

OMIM: gene MIM:611715 | disease phenotypes: MIM:612379, MIM:612713, MIM:213000, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
SRD5A3-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
SRD5A3-congenital disorder of glycosylation	Definitive	AR

Mondo (8): SRD5A3-congenital disorder of glycosylation (MONDO:0012885), congenital nervous system disorder (MONDO:0002320), Kahrizi syndrome (MONDO:0012991), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), congenital disorder of glycosylation (MONDO:0015286), cone dystrophy (MONDO:0000455), autism (MONDO:0005260), retinal disorder (MONDO:0005283)

Orphanet (6): SRD5A3-CDG (Orphanet:324737), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Congenital disorder of glycosylation (Orphanet:137), Progressive cone dystrophy (Orphanet:1871), Kahrizi syndrome (Orphanet:168972)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000316	Hypertelorism
HP:0000329	Facial hemangioma
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000572	Visual loss
HP:0000589	Coloboma
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000677	Oligodontia
HP:0000821	Hypothyroidism
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000973	Cutis laxa
HP:0000982	Palmoplantar keratoderma
HP:0000998	Hypertrichosis
HP:0001000	Abnormality of skin pigmentation
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST005962_39	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST010320_77	PR interval	3.000000e-09
GCST010321_209	PR interval	6.000000e-10
GCST010699_101	Brain morphology (min-P)	1.000000e-11
GCST010701_29	Cortical surface area (MOSTest)	2.000000e-31
GCST010702_108	Subcortical volume (MOSTest)	1.000000e-09
GCST010703_345	Brain morphology (MOSTest)	4.000000e-10
GCST90020025_312	Waist-to-hip ratio adjusted for BMI	6.000000e-09
GCST90020025_313	Waist-to-hip ratio adjusted for BMI	9.000000e-09
GCST90020025_314	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90020025_315	Waist-to-hip ratio adjusted for BMI	6.000000e-13
GCST90020025_316	Waist-to-hip ratio adjusted for BMI	5.000000e-10
GCST90020025_318	Waist-to-hip ratio adjusted for BMI	1.000000e-15
GCST90020026_280	Hip index	2.000000e-13
GCST90020026_282	Hip index	4.000000e-11
GCST90020027_1887	Waist-hip index	2.000000e-09
GCST90020027_1888	Waist-hip index	3.000000e-09
GCST90020027_1889	Waist-hip index	2.000000e-09
GCST90020027_1890	Waist-hip index	4.000000e-13
GCST90020027_1891	Waist-hip index	6.000000e-10
GCST90020027_1893	Waist-hip index	3.000000e-16
GCST90020028_1924	Hip circumference adjusted for BMI	7.000000e-09
GCST90020028_1925	Hip circumference adjusted for BMI	4.000000e-10
GCST90020028_1926	Hip circumference adjusted for BMI	1.000000e-10
GCST90020028_1928	Hip circumference adjusted for BMI	2.000000e-09
GCST90020028_1929	Hip circumference adjusted for BMI	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004462	PR interval
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
D012164	Retinal Diseases	C11.768
C562568	Cerebellar Hypoplasia (supp.)
C567196	Kahrizi Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363075 (PROTEIN FAMILY)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases abundance	2
Arsenic	decreases methylation, increases abundance, decreases expression	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Cadmium Chloride	affects expression, decreases expression	2
allyl 2,4,6-tribromophenyl ether	decreases expression	1
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	decreases expression, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
quercitrin	increases expression	1
sulforaphane	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	decreases expression	1
K 7174	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
2,3-dibromopropyl-2,4,6-tribromophenyl ether	decreases expression	1
NSC 689534	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Cidofovir	decreases expression	1
Acetaminophen	decreases expression	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, increases expression	1
Coumestrol	increases expression, affects cotreatment	1
Clodronic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3592007	Binding	Inhibition of 5alpha-reductase in human epidermis assessed as inhibition of [14C]testosterone to DHT after 24 hrs	A full conformational characterization of antiandrogen cortexolone-17-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy — Medchemcomm

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms