AKR1D1

Summary

AKR1D1 (aldo-keto reductase family 1 member D1, HGNC:388) is a protein-coding gene on chromosome 7q33, encoding Aldo-keto reductase family 1 member D1 (P51857). Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction.

The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet.

Source: NCBI Gene 6718 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital bile acid synthesis defect 2 (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 245 total — 9 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_005989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:388
Approved symbol	AKR1D1
Name	aldo-keto reductase family 1 member D1
Location	7q33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000122787
Ensembl biotype	protein_coding
OMIM	604741
Entrez	6718

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000242375, ENST00000411726, ENST00000432161, ENST00000438242, ENST00000468877, ENST00000470851, ENST00000885435, ENST00000885436, ENST00000885437, ENST00000885438, ENST00000885439, ENST00000885440, ENST00000885441, ENST00000885442

RefSeq mRNA: 3 — MANE Select: NM_005989 NM_001190906, NM_001190907, NM_005989

CCDS: CCDS55169, CCDS55170, CCDS5846

Canonical transcript exons

ENST00000242375 — 9 exons

Exon	Start	End
ENSE00001637760	138088601	138088768
ENSE00001715511	138091768	138091884
ENSE00001894873	138076459	138076611
ENSE00003481821	138106608	138106717
ENSE00003482179	138113690	138113772
ENSE00003575675	138097866	138097943
ENSE00003656652	138105307	138105429
ENSE00003657359	138107415	138107580
ENSE00003850388	138116620	138118305

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 95.13.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4831 / max 209.2642, expressed in 23 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81398	0.1798	13
81399	0.1777	12
81397	0.1115	7
81392	0.0141	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	95.13	gold quality
right lobe of liver	UBERON:0001114	93.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.33	gold quality
right testis	UBERON:0004534	69.29	gold quality
left testis	UBERON:0004533	68.85	gold quality
testis	UBERON:0000473	67.16	gold quality
buccal mucosa cell	CL:0002336	58.83	silver quality
decidua	UBERON:0002450	56.55	gold quality
endometrium epithelium	UBERON:0004811	55.91	gold quality
stromal cell of endometrium	CL:0002255	53.58	silver quality
hair follicle	UBERON:0002073	52.43	gold quality
lower lobe of lung	UBERON:0008949	51.42	silver quality
quadriceps femoris	UBERON:0001377	50.50	gold quality
pancreatic ductal cell	CL:0002079	50.45	silver quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
vastus lateralis	UBERON:0001379	49.69	gold quality
colonic epithelium	UBERON:0000397	49.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
deltoid	UBERON:0001476	49.23	silver quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
thymus	UBERON:0002370	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting AKR1D1, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3133	99.81	70.92	3506

Literature-anchored findings (GeneRIF, showing 26)

• In placenta and myometrium, relative expression decreased significantly in association with labour, by about two-fold and 10-fold, respectively. These data are consistent with a possible role for 5betaDHP in the onset of spontaneous human labour. (PMID:16123077)
• analysis of human liver Delta4-3-ketosteroid 5beta-reductase (AKR1D1) crystal structure and implications for substrate binding and catalysis (PMID:18407998)
• The structures of an AKR1D1-NADP(+) binary complex, and AKR1D1-NADP(+)-cortisone, AKR1D1-NADP(+)-progesterone and AKR1D1-NADP(+)-testosterone ternary complexes at high resolutions, is reported. (PMID:18848863)
• Structure determination of human AKR1C4 and homology modelling of AKR1D1 followed by docking experiments were used to explore active site geometries. (PMID:19013211)
• Delta4-3-ketosteroid 5beta-reductase (AKR1D1) has an alternative binding site responsible for substrate inhibition (PMID:19075558)
• SRD5B1 gene analysis needed for the accurate diagnosis of primary 3-oxo-Delta4-steroid 5beta-reductase deficiency. (PMID:19175828)
• analysis of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency (PMID:20522910)
• all five mutations identified in patients with functional bile acid deficiency strongly affected AKR1D1 enzyme functionality and therefore may be causal for this disease (PMID:21185810)
• determined the substrate specificity of homogeneous human recombinant AKR1D1 using C18, C19, C21, and C27 Delta(4)-ketosteroids and assessed the pH-rate dependence of the enzyme. (PMID:21255593)
• These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference. (PMID:22437839)
• Novel homozygous frameshift mutations in the AKR1D1 gene and in the SKIV2L gene were found in a family with severe infantile liver disease. (PMID:23679950)
• Consistent with AKR1D1’s putative role as a driver of the P450 subnetwork, the AKR1D1 3’-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple P450s (PMID:23704699)
• Studies indicate that mutations in aldo-keto reductase family 1 (AKR1) enzymes AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency. (PMID:24189185)
• AKR1D1 generates all 5beta-dihydrosteroids in the C19-C27 steroid series. (PMID:24513054)
• Despite having high kchem values with steroid hormones, the kinetic control of AKR1D1 is consistent with the enzyme catalysing the slowest step in the catabolic sequence of steroid hormone transformation in the liver. (PMID:24894951)
• When different steroid substrates were used in single turnover experiments with AKR1D1. (PMID:25500266)
• Impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation in AKR1D1. (PMID:26418565)
• infant proved to be a compound heterozygote of the AKR1D1 variants c.579+2delT and c.853C>T(p.Q285X), two novel mutations originated from his mother and father, respectively (PMID:28697823)
• dysregulation of AKR1D1 disrupted bile acid and steroid hormone homeostasis, which may contribute to the pathogenesis of diabetes. (PMID:29024782)
• AKR1D1 regulates glucocorticoid availability in human hepatoma cells. AKR1D1 regulates glucocorticoid receptor activation in human hepatoma cells. (PMID:30769091)
• The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(-)-IBP was evaluated. (PMID:31259734)
• may have a crucial role in the pathogenesis and progression of the non-alcoholic fatty liver disease. (PMID:31330134)
• AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases. (PMID:31337596)
• Diagnostic and prognostic values of AKR1C3 and AKR1D1 in hepatocellular carcinoma. (PMID:33493134)
• Differential activity and expression of human 5beta-reductase (AKR1D1) splice variants. (PMID:33502336)
• Recurrent AKR1D1 c.580-13T>A Variant: A Cause of Delta[4]-3-Oxosteroid-5beta-Reductase Deficiency. (PMID:36739965)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
mus_musculus	Akr1d1	ENSMUSG00000038641
rattus_norvegicus	Akr1d1	ENSRNOG00000013004
drosophila_melanogaster	CG18547	FBGN0037973
drosophila_melanogaster	CG3397	FBGN0037975
caenorhabditis_elegans		WBGENE00003176
caenorhabditis_elegans		WBGENE00009980
caenorhabditis_elegans		WBGENE00009981
caenorhabditis_elegans		WBGENE00012722
caenorhabditis_elegans		WBGENE00012723
caenorhabditis_elegans		WBGENE00015307

Paralogs (16): AKR7A2 (ENSG00000053371), KCNAB2 (ENSG00000069424), AKR1B1 (ENSG00000085662), AKR1A1 (ENSG00000117448), AKR1C2 (ENSG00000151632), AKR7A3 (ENSG00000162482), AKR1E2 (ENSG00000165568), KCNAB1 (ENSG00000169282), KCNAB3 (ENSG00000170049), AKR1C1 (ENSG00000187134), AKR1C3 (ENSG00000196139), AKR1B10 (ENSG00000198074), AKR1C4 (ENSG00000198610), AKR7L (ENSG00000211454), AKR1B15 (ENSG00000227471), AKR1C8 (ENSG00000264006)

Protein

Protein identifiers

Aldo-keto reductase family 1 member D1 — P51857 (reviewed: P51857)

Alternative names: 3-oxo-5-beta-steroid 4-dehydrogenase, Delta(4)-3-ketosteroid 5-beta-reductase, Delta(4)-3-oxosteroid 5-beta-reductase

All UniProt accessions (2): C9J3U1, P51857

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. Capable of reducing a broad range of delta-(4)-3-ketosteroids from C18 (such as, 17beta-hydroxyestr-4-en-3-one) to C27 (such as, 7alpha-hydroxycholest-4-en-3-one).

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in liver. Expressed in testis and weakly in colon.

Disease relevance. Congenital bile acid synthesis defect 2 (CBAS2) [MIM:235555] A condition characterized by jaundice, intrahepatic cholestasis and hepatic failure. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to inhibition by high substrate concentrations. Inhibited by testosterone concentrations above 10 uM. Inhibited by the primary and secondary bile acids chenodeoxycholic acid and ursodeoxycholic acid.

Similarity. Belongs to the aldo/keto reductase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P51857-1	1	yes
P51857-2	2
P51857-3	3

RefSeq proteins (3): NP_001177835, NP_001177836, NP_005980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018170	Aldo/ket_reductase_CS	Conserved_site
IPR020471	AKR	Family
IPR023210	NADP_OxRdtase_dom	Domain
IPR036812	NAD(P)_OxRdtase_dom_sf	Homologous_superfamily
IPR044483	AKR1D1	Family

Pfam: PF00248

Enzyme classification (BRENDA):

• EC 1.3.1.3 — DELTA4-3-oxosteroid 5beta-reductase (BRENDA: 16 organisms, 83 substrates, 29 inhibitors, 78 Km, 53 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROGESTERONE	0.0022–0.362	14
2-CYCLOHEXEN-1-ONE	0.116–1.15	9
TESTOSTERONE	0.0016–0.0127	9
CORTISONE	0.0013–0.034	8
4-ANDROSTENE-3,17-DIONE	0.0009–2.193	7
NADPH	0.003–0.085	7
CORTISOL	0.0071–2.079	6
ANDROSTENEDIONE	0.0004–0.0163	3
CORTEXONE	1.597–2.373	2
1,4-ANDROSTADIEN-17BETA-OL-3-ONE	0.0032	1
4-CHOLESTEN-7ALPHA-OL-3-ONE	0.0008	1
4-ESTREN-17BETA-OL-3-ONE	0.003	1
7ALPHA,12ALPHA-DIHYDROXY-4-CHOLESTEN-3-ONE	0.0122	1
7ALPHA-HYDROXY-4-CHOLESTEN-3-ONE	0.0091	1
ALDOSTERONE	0.0025	1

Catalyzed reactions (Rhea), 12 shown:

• 5beta-cholestan-3-one + NADP(+) = cholest-4-en-3-one + NADPH + H(+) (RHEA:11524)
• 4,5beta-dihydrocortisone + NADP(+) = cortisone + NADPH + H(+) (RHEA:14037)
• 7alpha,12alpha-dihydroxycholest-4-en-3-one + NADPH + H(+) = 7alpha,12alpha-dihydroxy-5beta-cholestan-3-one + NADP(+) (RHEA:46632)
• 5beta-dihydrotestosterone + NADP(+) = testosterone + NADPH + H(+) (RHEA:46636)
• 7alpha-hydroxycholest-4-en-3-one + NADPH + H(+) = 7alpha-hydroxy-5beta-cholestan-3-one + NADP(+) (RHEA:46640)
• cortisol + NADPH + H(+) = 5beta-dihydrocortisol + NADP(+) (RHEA:46644)
• epitestosterone + NADPH + H(+) = 5beta-dihydroepitestosterone + NADP(+) (RHEA:46652)
• androst-4-ene-3,17-dione + NADPH + H(+) = 5beta-androstane-3,17-dione + NADP(+) (RHEA:46656)
• progesterone + NADPH + H(+) = 5beta-pregnan-3,20-dione + NADP(+) (RHEA:46660)
• corticosterone + NADPH + H(+) = 5beta-dihydrocorticosterone + NADP(+) (RHEA:46664)
• 21-hydroxyprogesterone + NADPH + H(+) = 5beta-dihydrodeoxycorticosterone + NADP(+) (RHEA:46668)
• aldosterone + NADPH + H(+) = 5beta-dihydroaldosterone + NADP(+) (RHEA:46672)

UniProt features (52 total): helix 16, binding site 12, strand 9, sequence variant 6, splice variant 2, mutagenesis site 2, turn 2, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
3BUV	X-RAY DIFFRACTION	1.35
3BUR	X-RAY DIFFRACTION	1.62
3UZX	X-RAY DIFFRACTION	1.64
3G1R	X-RAY DIFFRACTION	1.7
3BV7	X-RAY DIFFRACTION	1.79
3UZZ	X-RAY DIFFRACTION	1.82
3UZY	X-RAY DIFFRACTION	1.83
3UZW	X-RAY DIFFRACTION	1.89
3CAV	X-RAY DIFFRACTION	1.9
3CMF	X-RAY DIFFRACTION	1.9
3CAS	X-RAY DIFFRACTION	2
3DOP	X-RAY DIFFRACTION	2
3COT	X-RAY DIFFRACTION	2.03
3CAQ	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51857-F1	97.15	0.96

Functional residue map

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

Catalytic / active sites (1): 58 (proton donor)

Ligand- & substrate-binding residues (12): 193; 219–224; 230; 273–283; 22–26; 26; 53; 58; 89; 120; 132; 169–170

Mutagenesis-validated functional residues (2):

Position	Phenotype
58	loss of activity.
120	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-193368	Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-HSA-193775	Synthesis of bile acids and bile salts via 24-hydroxycholesterol
R-HSA-193807	Synthesis of bile acids and bile salts via 27-hydroxycholesterol
R-HSA-1430728	Metabolism
R-HSA-192105	Synthesis of bile acids and bile salts
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 225 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_DIGESTION, MODULE_97, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, MODULE_182, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, CEBPB_01, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MORF_ZNF10, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (12): bile acid biosynthetic process (GO:0006699), cholesterol catabolic process (GO:0006707), digestion (GO:0007586), C21-steroid hormone metabolic process (GO:0008207), androgen metabolic process (GO:0008209), bile acid catabolic process (GO:0030573), alcohol metabolic process (GO:0006066), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), lipid catabolic process (GO:0016042), monocarboxylic acid metabolic process (GO:0032787), hormone metabolic process (GO:0042445)

GO Molecular Function (8): aldose reductase (NADPH) activity (GO:0004032), steroid binding (GO:0005496), alcohol dehydrogenase (NADP+) activity (GO:0008106), steroid dehydrogenase activity (GO:0016229), ketosteroid monooxygenase activity (GO:0047086), Delta4-3-oxosteroid 5beta-reductase activity (GO:0047787), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	3
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bile acid metabolic process	2
steroid metabolic process	2
hormone metabolic process	2
lipid metabolic process	2
cellular anatomical structure	2
monocarboxylic acid biosynthetic process	1
cholesterol metabolic process	1
sterol catabolic process	1
alcohol catabolic process	1
multicellular organismal process	1
monocarboxylic acid catabolic process	1
small molecule metabolic process	1
primary metabolic process	1
catabolic process	1
carboxylic acid metabolic process	1
metabolic process	1
regulation of hormone levels	1
alcohol dehydrogenase (NADP+) activity	1
lipid binding	1
alcohol dehydrogenase [NAD(P)+] activity	1
oxidoreductase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen	1
enone reductase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKR1D1	HSD3B7	Q9H2F3	956
AKR1D1	SRD5A1	P18405	888
AKR1D1	AMACR	Q9UHK6	822
AKR1D1	HSD11B1	P28845	753
AKR1D1	HSD11B2	P80365	752
AKR1D1	BAAT	Q14032	722
AKR1D1	PTN	P21246	719
AKR1D1	H6PD	O95479	706
AKR1D1	ABCB11	O95342	651
AKR1D1	ATP8B1	O43520	648
AKR1D1	CYP7A1	P22680	594
AKR1D1	ABCB4	P21439	591
AKR1D1	CYP7B1	O75881	588
AKR1D1	CYP27A1	Q02318	587
AKR1D1	CYP8B1	Q9UNU6	585

IntAct

12 interactions, top by confidence:

A	B	Type	Score
AKR1C3	AKR1C4	psi-mi:“MI:0914”(association)	0.620
AKR1C1	AKR1D1	psi-mi:“MI:0915”(physical association)	0.590
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
AKR1D1	AKR1B10	psi-mi:“MI:0914”(association)	0.530
AKR1C3	AKR1D1	psi-mi:“MI:0914”(association)	0.530
AKR1D1	DIRAS1	psi-mi:“MI:0914”(association)	0.530

BioGRID (26): SIRT1 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), AKR1B10 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), SIRT1 (Affinity Capture-MS), AKR1B10 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3B1EFQ1, A2XRZ0, A2XRZ6, B8ASB2, C6TBN2, F4HPY8, M2YJQ2, O22707, O23016, O70473, O81884, P02532, P07943, P0A9T4, P14550, P15122, P17264, P27800, P38918, P40691, P45376, P49249, P50578, P51635, P51857, Q01752, Q09923, Q0JE32, Q0PGJ6, Q28FD1, Q3L181, Q3ZCJ2, Q40648, Q42942, Q568L5, Q5R5D5, Q5ZK84, Q6AZW2, Q6GMC7, Q6UEH5

Diamond homologs: A0A1D5XGW0, A0A1X9QHJ0, A0A2P1GIY9, A0A9E7S518, A0A9E7S5B9, B4F9A4, B9VRJ2, C9JRZ8, D3ZF77, E7C196, H9JTG9, M9PF61, O08782, O32210, O34678, O49133, O60218, O70473, O80944, P02532, P05980, P07943, P0DKI7, P0DXG9, P0DXH7, P14065, P14550, P15121, P15122, P16116, P17264, P17516, P21300, P23457, P23901, P26690, P28475, P31867, P42330, P45376

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	15
Uncertain significance	130
Likely benign	29
Benign	37

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
4293811	NM_005989.4(AKR1D1):c.238del (p.Glu80fs)	Pathogenic
4525818	NM_005989.4(AKR1D1):c.580-13T>A	Pathogenic
4774003	NM_005989.4(AKR1D1):c.350dup (p.Tyr117Ter)	Pathogenic
5375	AKR1D1, 1-BP DEL, 511T	Pathogenic
5376	NM_005989.4(AKR1D1):c.316C>T (p.Leu106Phe)	Pathogenic
60298	GRCh38/hg38 7q33-34(chr7:137741740-139688885)x1	Pathogenic
815017	GRCh37/hg19 7q31.1-36.3(chr7:109251060-159119707)x3	Pathogenic
815042	GRCh37/hg19 7q33-34(chr7:135677938-139810886)x1	Pathogenic
915290	NM_005989.4(AKR1D1):c.267G>A (p.Trp89Ter)	Pathogenic
1066867	NM_005989.4(AKR1D1):c.262-1G>T	Likely pathogenic
1323872	NM_005989.4(AKR1D1):c.864del (p.Ser290fs)	Likely pathogenic
2633903	NM_005989.4(AKR1D1):c.579+2_579+4delinsA	Likely pathogenic
2832975	NM_005989.4(AKR1D1):c.689+1G>A	Likely pathogenic
288160	NM_005989.4(AKR1D1):c.261+1G>T	Likely pathogenic
2910216	NM_005989.4(AKR1D1):c.919C>T (p.Arg307Cys)	Likely pathogenic
3362334	NM_005989.4(AKR1D1):c.141_142del (p.Gly48fs)	Likely pathogenic
3594299	NM_005989.4(AKR1D1):c.174_175del (p.Tyr58_Gln59delinsTer)	Likely pathogenic
4081100	NM_005989.4(AKR1D1):c.261+2T>C	Likely pathogenic
4535962	NM_005989.4(AKR1D1):c.158A>G (p.Asp53Gly)	Likely pathogenic
500408	NM_005989.4(AKR1D1):c.93+1G>T	Likely pathogenic
501093	NM_005989.4(AKR1D1):c.580-1G>A	Likely pathogenic
501941	NM_005989.4(AKR1D1):c.980G>T (p.Ter327Leu)	Likely pathogenic
596094	NM_005989.4(AKR1D1):c.843del (p.Glu282fs)	Likely pathogenic
800839	NM_005989.4(AKR1D1):c.940T>C (p.Trp314Arg)	Likely pathogenic

SpliceAI

1380 predictions. Top by Δscore:

Variant	Effect	Δscore
7:138076612:G:GG	donor_gain	1.0000
7:138076612:G:T	donor_loss	1.0000
7:138076613:T:A	donor_loss	1.0000
7:138091762:TTTCA:T	acceptor_loss	1.0000
7:138091764:TCA:T	acceptor_loss	1.0000
7:138091765:CAG:C	acceptor_loss	1.0000
7:138091766:A:AG	acceptor_gain	1.0000
7:138091766:A:C	acceptor_loss	1.0000
7:138091767:G:GC	acceptor_gain	1.0000
7:138091767:G:GT	acceptor_loss	1.0000
7:138091767:GC:G	acceptor_gain	1.0000
7:138091767:GCT:G	acceptor_gain	1.0000
7:138091767:GCTA:G	acceptor_gain	1.0000
7:138091767:GCTAT:G	acceptor_gain	1.0000
7:138091881:TAAGG:T	donor_loss	1.0000
7:138091883:AGG:A	donor_loss	1.0000
7:138091885:GTGA:G	donor_loss	1.0000
7:138091886:T:G	donor_loss	1.0000
7:138097862:TCA:T	acceptor_loss	1.0000
7:138097864:A:AG	acceptor_gain	1.0000
7:138097865:G:A	acceptor_loss	1.0000
7:138097865:G:GT	acceptor_gain	1.0000
7:138097865:GC:G	acceptor_gain	1.0000
7:138097865:GCCA:G	acceptor_gain	1.0000
7:138097939:GGGAG:G	donor_gain	1.0000
7:138097940:GGAG:G	donor_gain	1.0000
7:138097940:GGAGG:G	donor_gain	1.0000
7:138097941:GAGG:G	donor_gain	1.0000
7:138097942:AGG:A	donor_loss	1.0000
7:138097944:G:GC	donor_loss	1.0000

AlphaMissense

2161 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:138097940:G:C	W151C	0.993
7:138097940:G:T	W151C	0.993
7:138097938:T:A	W151R	0.991
7:138097938:T:C	W151R	0.991
7:138105361:T:C	F171L	0.989
7:138105363:T:A	F171L	0.989
7:138105363:T:G	F171L	0.989
7:138105355:T:C	S169P	0.986
7:138088754:T:C	F83L	0.983
7:138088756:C:A	F83L	0.983
7:138088756:C:G	F83L	0.983
7:138107509:T:C	F262L	0.981
7:138107511:C:A	F262L	0.981
7:138107511:C:G	F262L	0.981
7:138091853:T:C	L116P	0.980
7:138097939:G:C	W151S	0.978
7:138107545:A:C	S274R	0.978
7:138107547:C:A	S274R	0.978
7:138107547:C:G	S274R	0.978
7:138091771:T:A	W89R	0.977
7:138091771:T:C	W89R	0.977
7:138088638:C:A	A44D	0.975
7:138105377:T:C	L176P	0.975
7:138107507:G:C	R261P	0.975
7:138116645:T:C	F322L	0.975
7:138116647:T:A	F322L	0.975
7:138116647:T:G	F322L	0.975
7:138088768:G:C	K87N	0.973
7:138088768:G:T	K87N	0.973
7:138105360:T:A	N170K	0.973

dbSNP variants (sampled 300 via entrez): RS1000092124 (7:138100963 C>T), RS1000114517 (7:138087853 C>T), RS1000115087 (7:138101282 C>A,T), RS1000142813 (7:138106263 TA>T,TAA), RS1000196564 (7:138081220 C>T), RS1000267492 (7:138093887 G>C), RS1000320520 (7:138107012 T>C), RS1000329686 (7:138074953 G>A), RS1000356810 (7:138118717 CA>C,CAA), RS1000440000 (7:138099144 G>A), RS1000519292 (7:138076446 T>A,C), RS1000566502 (7:138080160 T>C), RS1000618891 (7:138079905 C>A), RS1000637337 (7:138112582 G>A), RS1000666822 (7:138112926 G>T)

Disease associations

OMIM: gene MIM:604741 | disease phenotypes: MIM:235555, MIM:607765

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital bile acid synthesis defect 2	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital bile acid synthesis defect 2	Definitive	AR

Mondo (2): congenital bile acid synthesis defect 2 (MONDO:0009339), congenital bile acid synthesis defect (MONDO:0018841)

Orphanet (2): Congenital bile acid synthesis defect type 2 (Orphanet:79303), Congenital bile acid synthesis defect (Orphanet:485631)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000107	Renal cyst
HP:0000952	Jaundice
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001406	Intrahepatic cholestasis
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001978	Extramedullary hematopoiesis
HP:0002014	Diarrhea
HP:0002240	Hepatomegaly
HP:0002570	Steatorrhea
HP:0002630	Fat malabsorption
HP:0002748	Rickets
HP:0002904	Hyperbilirubinemia
HP:0002908	Conjugated hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003256	Abnormality of the coagulation cascade
HP:0003623	Neonatal onset
HP:0003645	Prolonged partial thromboplastin time
HP:0006579	Prolonged neonatal jaundice
HP:0008151	Prolonged prothrombin time
HP:0008897	Postnatal growth retardation
HP:0011040	Abnormal intrahepatic bile duct morphology
HP:0012379	Abnormal circulating enzyme concentration or activity
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0030984	Abnormal serum bile acid concentration
HP:0040319	Dark urine

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001715_11	Bipolar disorder with mood-incongruent psychosis	5.000000e-06
GCST003211_2	C-reactive protein levels in ischemic stroke	7.000000e-08
GCST010396_197	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535443	Bile acid synthesis defect, congenital, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066875 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.14	Kd	71.92	nM	CHEMBL3752910
7.14	ED50	71.92	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149825: Binding affinity to human AKR1D1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0719	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, affects expression	6
Cyclosporine	affects cotreatment, decreases expression	6
Aflatoxin B1	affects expression, decreases expression, decreases methylation	5
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
7 alpha-hydroxy-4-cholesten-3-one	decreases reaction, increases metabolic processing, affects cotreatment, increases reduction	2
bisphenol A	affects expression, decreases methylation	2
Acetaminophen	decreases expression, affects cotreatment	2
Chenodeoxycholic Acid	affects cotreatment, decreases expression	2
Deoxycholic Acid	affects cotreatment, decreases expression	2
Estradiol	decreases expression	2
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	2
Glycocholic Acid	affects cotreatment, decreases expression	2
Glycodeoxycholic Acid	affects cotreatment, decreases expression	2
Testosterone	increases metabolic processing, affects cotreatment, increases reduction, decreases reaction	2
cholest-4-en-3-one	increases reduction, affects cotreatment	1
OTX015	decreases expression	1
larotrectinib	affects activity	1
mivebresib	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
tri-o-cresyl phosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
periodate-oxidized adenosine	affects 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
CHEMBL5652867	Binding	Binding affinity to human AKR1D1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns