AMACR

Summary

AMACR (alpha-methylacyl-CoA racemase, HGNC:451) is a protein-coding gene on chromosome 5p13.2, encoding Alpha-methylacyl-CoA racemase (Q9UHK6). Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters.

This gene encodes a racemase. The encoded enzyme interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Encoded proteins from this locus localize to both mitochondria and peroxisomes. Mutations in this gene may be associated with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the upstream neighboring C1QTNF3 (C1q and tumor necrosis factor related protein 3) gene.

Source: NCBI Gene 23600 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alpha-methylacyl-CoA racemase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 300 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 59
• MANE Select transcript: NM_014324

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:451
Approved symbol	AMACR
Name	alpha-methylacyl-CoA racemase
Location	5p13.2
Locus type	gene with protein product
Status	Approved
Aliases	RACE, P504S
Ensembl gene	ENSG00000242110
Ensembl biotype	protein_coding
OMIM	604489
Entrez	23600

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000335606, ENST00000382072, ENST00000382085, ENST00000502637, ENST00000506639, ENST00000514195, ENST00000926930

RefSeq mRNA: 3 — MANE Select: NM_014324 NM_001167595, NM_014324, NM_203382

CCDS: CCDS3902, CCDS3903, CCDS54836

Canonical transcript exons

ENST00000335606 — 5 exons

Exon	Start	End
ENSE00001816051	33986165	33989502
ENSE00001953485	34007773	34008050
ENSE00004474277	34005756	34005899
ENSE00004474279	33998641	33998827
ENSE00004474286	34004574	34004734

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 94.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7445 / max 491.4051, expressed in 1695 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61232	5.4118	1609
61233	2.1548	1310
61231	0.1778	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adult mammalian kidney	UBERON:0000082	94.88	gold quality
rectum	UBERON:0001052	93.87	gold quality
kidney	UBERON:0002113	92.22	gold quality
liver	UBERON:0002107	92.18	gold quality
mucosa of transverse colon	UBERON:0004991	91.75	gold quality
right lobe of liver	UBERON:0001114	91.09	gold quality
islet of Langerhans	UBERON:0000006	90.16	gold quality
calcaneal tendon	UBERON:0003701	89.16	gold quality
fundus of stomach	UBERON:0001160	87.86	gold quality
cortex of kidney	UBERON:0001225	87.75	gold quality
gall bladder	UBERON:0002110	87.65	gold quality
body of stomach	UBERON:0001161	87.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.25	gold quality
duodenum	UBERON:0002114	87.15	gold quality
metanephros cortex	UBERON:0010533	85.95	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.83	gold quality
right adrenal gland cortex	UBERON:0035827	85.44	gold quality
stomach	UBERON:0000945	85.38	gold quality
transverse colon	UBERON:0001157	85.08	gold quality
right adrenal gland	UBERON:0001233	84.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.11	gold quality
left adrenal gland	UBERON:0001234	83.53	gold quality
left adrenal gland cortex	UBERON:0035825	82.93	gold quality
adrenal gland	UBERON:0002369	82.58	gold quality
adrenal tissue	UBERON:0018303	81.84	gold quality
endometrium	UBERON:0001295	81.83	gold quality
esophagus mucosa	UBERON:0002469	81.52	gold quality
pancreas	UBERON:0001264	81.41	gold quality
cortical plate	UBERON:0005343	81.29	gold quality
colon	UBERON:0001155	81.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	352.42
E-MTAB-8495	yes	117.99
E-HCAD-10	yes	32.93
E-ANND-3	yes	4.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR3C1, SP1, ZNF202

miRNA regulators (miRDB)

76 targeting AMACR, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-6126	99.62	68.09	996

Literature-anchored findings (GeneRIF, showing 40)

• AMACR was shown to be overexpressed in prostate cancer (PMID:11926890)
• AMACR expression may be a marker of tumor differentiation (PMID:12213712)
• expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone (PMID:12673556)
• AMACR was overexpressed in prostate cancer. One AMACR probeset from an alternatively spliced exon had 88% identity to a 521-bp sequence spanning 4 exons of fumarate hydratase. The predicted sequence revealed a new GLGELIL peptide shared by both proteins. (PMID:12810662)
• Data suggest that AMACR is essential for optimal growth of prostate cancer cells in vitro and that this enzyme has the potential to be a complementary target with androgen ablation in PCa treatment. (PMID:14612535)
• AMACR (P504S) has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma (PMID:15323145)
• Results demonstrated the promising features of AMACR as a biomarker for prostate cancer in this large series and the potential to develop automated quantitative diagnostic tests. (PMID:15330799)
• Novel variant of AMACR identified; real time PCR demonstrates that this splice variant is expressed in tumor, normal prostate tissue, and PC3 cell lines (PMID:15880524)
• AMACR protein is expressed in normal breast and its expression seems to increase in invasive carcinomas (PMID:15941950)
• AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer (PMID:15941951)
• AMACR immunoreactivity may be useful in differentiating papillary renal cell carcinoma from metanephric adenoma. (PMID:16424894)
• expression of PSGR and PSGR2 relative to AMACR in prostate cancer; AMACR was the most overexpressed, but in some cases expression of AMACR was not significantly elevated while PSGR and/or PSGR2 were substantially elevated (PMID:16491480)
• Moderate to strong P504S expression in high-grade prostatic intraepithelial neoplasia of biopsy specimens is indicative of an associated adenocarcinoma. (PMID:16506014)
• AMACR immunohistochemical staining has shown the ability to improve detection of small focal prostatic carcinoma that could be missed by conventional histological examination. (PMID:16681682)
• Increase in AMACR expression is associated with prostate cancer (PMID:17067752)
• Expression in prostatic cancer shows a correlation with Gleason severity score. (PMID:17222253)
• AMACR overexpression in colorectal carcinoma is correlated with tumor differentiation. (PMID:17525630)
• AMACR gene variants were unrelated to prostate cancer overall in this study. (PMID:17680641)
• Our results confirm an initial report of association between the AMACR gene and the risk of familial prostate cancer. (PMID:17683075)
• Variants in AMACR associated with advanced distal colorectal adenoma were identified and pointed to potential interactions with iburpofen use. (PMID:17684125)
• Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder. (PMID:18032455)
• promoter function of AMACR is independent of androgen receptor-mediated signaling (PMID:18080842)
• Review about the role of AMACR in the branched-chain fatty amino acids metabolism and its link with cancer. (PMID:18279392)
• AMACR expression may be a new diagnostic marker for dysplasia carcinoma sequence in Barrett’s low-grade neoplastic lesions. (PMID:18500268)
• In a relatively genetically homogenous Tasmanian population, there is evidence for a significant association between variants within the AMACR gene and prostate cancer risk. (PMID:18537123)
• Increased AMACR expression and its association with tumor venous invasion suggest that alpha-Methylacyl-CoA racemase may play a role in hepatocellular carcinoma development and progression. (PMID:18577240)
• Overexpression of alpha-methylacyl-CoA racemase ia a useful parameter for identifying dysplasia in Barrett esophagus. (PMID:18665038)
• AMACR expression in colorectal cancer was significantly associated with tumor grade, stage, non-mucinous phenotype, and left-sided tumor localization. AMACR staining results were unrelated to clinical outcome. (PMID:18712414)
• The high level expression of AMACR in high-grade dysplasia and carcinoma suggests that it may be a useful biomarker in distinguishing high-grade dysplasia and carcinoma from low-grade dysplasia. (PMID:18785113)
• The immunohistochemical profile of clear cell carcinomas of the urinary tract…is positive for P504S (PMID:18788852)
• combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease. (PMID:18835622)
• Immunohistochemistry with anti-AMACR/TO63 is useful for detecting prostate cancer in the full range of prostate specimens encountered in needle biopsies. (PMID:19068396)
• deregulation of Alpha-methylacyl-coenzyme A racemase during colon carcinogenesis involves two nonrandom events, resulting in the mutually exclusive existence of double-deletion at CG3 and CG10 and deletion of CG12-16 in a newly identified CpG island (PMID:19148275)
• AMACR immunostaining does not seem to be a useful marker in distinguishing nephrogenic adenoma from prostatic adenocarcinoma (PMID:19384190)
• P504S/AMACR staining might be of great value in cytodiagnosis of prostate lesions (PMID:19459159)
• AMACR showed diffuse or focal positivity in cancer, high-grade prostatic intraepithelial neoplasia, and atypia (PMID:19605815)
• The expression of AMACR is increased in benign sebaceous glands and sebaceous hyperplasia; with decreasing AMACR expression in tumors with less sebaceous differentiation (PMID:19638170)
• marker of differential diagnosis of kidney cancer (PMID:20102405)
• Our study showed that 34betaE12 is the most appropriate negative marker to combine with AMACR as a positive marker for the diagnosis of prostate adenocarcinoma. (PMID:20189848)
• study showed that 34betaE12 is the most appropriate negative marker to combine with alpha-methylacyl coenzyme A racemase as a positive marker for the diagnosis of prostate adenocarcinoma[34betaE12] (PMID:20189848)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	amacr	ENSDARG00000057435
mus_musculus	Amacr	ENSMUSG00000022244
rattus_norvegicus	Amacr	ENSRNOG00000018662
drosophila_melanogaster	Amacr	FBGN0032881
caenorhabditis_elegans		WBGENE00014128
caenorhabditis_elegans		WBGENE00016034

Paralogs (1): SUGCT (ENSG00000175600)

Protein

Protein identifiers

Alpha-methylacyl-CoA racemase — Q9UHK6 (reviewed: Q9UHK6)

Alternative names: 2-methylacyl-CoA racemase

All UniProt accessions (2): D6RB81, Q9UHK6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters. Acts only on coenzyme A thioesters, not on free fatty acids, and accepts as substrates a wide range of alpha-methylacyl-CoAs, including pristanoyl-CoA, trihydroxycoprostanoyl-CoA (an intermediate in bile acid synthesis), and arylpropionic acids like the anti-inflammatory drug ibuprofen (2-(4-isobutylphenyl)propionic acid) but neither 3-methyl-branched nor linear-chain acyl-CoAs.

Subunit / interactions. Monomer.

Subcellular location. Peroxisome. Mitochondrion.

Disease relevance. Alpha-methylacyl-CoA racemase deficiency (AMACRD) [MIM:614307] A rare autosomal recessive peroxisomal disorder characterized by elevated plasma concentrations of pristanic acid C27-bile-acid intermediates, and adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. The disease is caused by variants affecting the gene represented in this entry. Congenital bile acid synthesis defect 4 (CBAS4) [MIM:214950] A disorder characterized by the presence of trihydroxycoprostanic acid in the bile and absence of cholic acid. Patients manifest neonatal jaundice, intrahepatic cholestasis and bile duct deficiency. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; bile acid biosynthesis. Lipid metabolism; fatty acid metabolism.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Expression is elevated in prostate cancer.

Similarity. Belongs to the CoA-transferase III family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UHK6-1	1	yes
Q9UHK6-2	2, IBLi
Q9UHK6-4	3
Q9UHK6-5	4

RefSeq proteins (3): NP_001161067, NP_055139, NP_976316 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003673	CoA-Trfase_fam_III	Family
IPR023606	CoA-Trfase_III_dom_1_sf	Homologous_superfamily
IPR044855	CoA-Trfase_III_dom3_sf	Homologous_superfamily
IPR050509	CoA-transferase_III	Family

Pfam: PF02515

Enzyme classification (BRENDA):

• EC 5.1.99.4 — alpha-methylacyl-CoA racemase (BRENDA: 5 organisms, 65 substrates, 143 inhibitors, 18 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(2R)-IBUPROFENOYL-COA	0.048–0.071	2
(2S)-IBUPROFENOYL-COA	0.086–0.087	2
(R)-2-METHYLDECANOYL-COA	0.277–1.2	2
(S)-2-METHYLDECANOYL-COA	0.614–1.2	2
PRISTANOYL-COA	0.076–0.172	2
TRIHYDROXYCOPROSTANOYL-COA	0.0316–0.06	2
(2S)-2-METHYLDECANOYL-COA	0.277	1
(R)-PRISTANOYL-COA	0.041	1
(S)-KETOPROFENOYL-COA	0.052	1
(S)-NAPROXENOYL-COA	0.068	1
3-FLUORO-2-METHYLDECANOYL-COA	0.021	1

Catalyzed reactions (Rhea), 3 shown:

• a (2S)-2-methylacyl-CoA = a (2R)-2-methylacyl-CoA (RHEA:12657)
• (25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oyl-CoA = (25S)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oyl-CoA (RHEA:40455)
• (2R,6)-dimethylheptanoyl-CoA = (2S,6)-dimethylheptanoyl-CoA (RHEA:46732)

UniProt features (34 total): sequence variant 11, sequence conflict 7, splice variant 5, modified residue 4, binding site 3, active site 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHK6-F1	95.79	0.95

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 (2): 122 (proton acceptor); 152 (proton donor)

Ligand- & substrate-binding residues (3): 36; 55–58; 121–126

Post-translational modifications (4): 268, 58, 87, 87

Function

Pathways and Gene Ontology

Reactome pathways

12 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-389887	Beta-oxidation of pristanoyl-CoA
R-HSA-9033241	Peroxisomal protein import
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-390918	Peroxisomal lipid metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids
R-HSA-8978868	Fatty acid metabolism
R-HSA-9609507	Protein localization

MSigDB gene sets: 321 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_OXIDASE, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, TGTGTGA_MIR377, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS

GO Biological Process (4): bile acid biosynthetic process (GO:0006699), bile acid metabolic process (GO:0008206), fatty acid beta-oxidation using acyl-CoA oxidase (GO:0033540), fatty acid metabolic process (GO:0006631)

GO Molecular Function (4): signaling receptor binding (GO:0005102), alpha-methylacyl-CoA racemase activity (GO:0008111), catalytic activity (GO:0003824), isomerase activity (GO:0016853)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	2
Metabolism of lipids	2
Peroxisomal lipid metabolism	1
Protein localization	1
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Fatty acid metabolism	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monocarboxylic acid metabolic process	2
cellular anatomical structure	2
cytoplasm	2
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
steroid metabolic process	1
fatty acid beta-oxidation	1
lipid metabolic process	1
protein binding	1
racemase and epimerase activity	1
molecular_function	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
microbody	1
peroxisome	1
microbody lumen	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1521 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMACR	OR51E2	Q9H255	905
AMACR	HSD3B7	Q9H2F3	879
AMACR	OR51E1	Q8TCB6	848
AMACR	AKR1D1	P51857	822
AMACR	KRT7	P08729	811
AMACR	KLK3	P07288	803
AMACR	HPN	P05981	749
AMACR	TMPRSS2	O15393	744
AMACR	KRT5	P13647	723
AMACR	MME	P08473	720
AMACR	SLC45A3	Q96JT2	703
AMACR	PAX8	Q06710	699
AMACR	KRT20	P35900	691
AMACR	CA9	Q16790	667
AMACR	TFE3	P19532	666

IntAct

7 interactions, top by confidence:

A	B	Type	Score
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
AMACR	FKBP5	psi-mi:“MI:0914”(association)	0.350
AMACR	VWA8	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
SLC37A3	PLXNB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (74): AMACR (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), PSMG3 (Affinity Capture-MS), PSMG4 (Affinity Capture-MS), AMACR (Affinity Capture-RNA), AMACR (Affinity Capture-MS), AMACR (Negative Genetic), AMACR (Affinity Capture-MS), PSMG4 (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), PSMG3 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), BCKDK (Affinity Capture-MS), GUF1 (Affinity Capture-MS)

ESM2 similar proteins: A0KPX1, A0L1P1, A1B5V3, A1REZ7, A1S2G0, A1U3G0, A3CZM2, A4SI57, A4Y2N7, A5F5M8, A5V3V0, A6WID2, A7MIF0, A7MXR2, A8HZS2, A9KY30, A9X6P9, B1ZLM1, B3Q9S4, B7KWB0, B7VJ04, B8E699, O06543, O09174, O68965, P76518, P9WMN6, P9WMN7, Q0AM22, Q0HE84, Q0HZR5, Q0VS01, Q133H2, Q135J7, Q1QL30, Q28V76, Q2G4F5, Q2YBM5, Q3SR31, Q5LU62

Diamond homologs: A0A2I6PIZ1, A1ADQ1, A4YXN2, A5EGD7, A6W2K8, A7ZPI2, A8A2M8, A9WC39, A9WC40, A9WGE3, A9X6P9, B1IX88, B1LMH0, B1X9P6, B2TWX3, B3QBS6, B5YYX4, B6I6S5, B6JE29, B7LBS7, B7M6P3, B7MH34, B7MY33, B7N5X4, B7NPQ8, B7UG84, C4ZVR1, G0HQ31, K3VD64, O06543, O87838, P69902, P69903, P76518, P95149, P96877, Q07Q82, Q0T2C3, Q0TF87, Q139H7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	156
Likely benign	101
Benign	17

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1460218	NC_000005.9:g.(?33982368)(33991527_?)del	Pathogenic
3062849	GRCh37/hg19 5p13.2(chr5:33955464-34058555)x1	Pathogenic
5524	NM_014324.6(AMACR):c.320T>C (p.Leu107Pro)	Pathogenic
3534565	NM_014324.6(AMACR):c.643_644insC (p.Gly215fs)	Likely pathogenic
4541037	NM_014324.6(AMACR):c.740-12_740-2delinsTGGACTTGGACTT	Likely pathogenic

SpliceAI

883 predictions. Top by Δscore:

Variant	Effect	Δscore
5:33989500:GTC:G	acceptor_gain	1.0000
5:33989502:CCTGA:C	acceptor_loss	1.0000
5:33989503:C:CC	acceptor_gain	1.0000
5:33989504:T:C	acceptor_loss	1.0000
5:33998637:TTA:T	donor_loss	1.0000
5:33998637:TTACC:T	donor_loss	1.0000
5:33998638:TA:T	donor_loss	1.0000
5:33998639:A:AC	donor_gain	1.0000
5:33998639:A:AT	donor_loss	1.0000
5:33998639:AC:A	donor_gain	1.0000
5:33998640:C:CA	donor_gain	1.0000
5:33998640:CC:C	donor_gain	1.0000
5:33998640:CCT:C	donor_gain	1.0000
5:33998640:CCTT:C	donor_gain	1.0000
5:33998640:CCTTT:C	donor_gain	1.0000
5:33998825:CAC:C	acceptor_gain	1.0000
5:33998825:CACCT:C	acceptor_gain	1.0000
5:33998826:ACC:A	acceptor_loss	1.0000
5:33998827:CC:C	acceptor_loss	1.0000
5:33998827:CCTT:C	acceptor_gain	1.0000
5:33998828:C:CA	acceptor_loss	1.0000
5:33998829:T:A	acceptor_loss	1.0000
5:33998829:T:C	acceptor_gain	1.0000
5:33998829:T:TC	acceptor_gain	1.0000
5:33998830:T:C	acceptor_gain	1.0000
5:33998830:T:TC	acceptor_gain	1.0000
5:33998839:C:CT	acceptor_gain	1.0000
5:34005751:CATA:C	donor_loss	1.0000
5:34005752:ATAC:A	donor_loss	1.0000
5:34005753:TA:T	donor_loss	1.0000

AlphaMissense

2486 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:34005779:T:A	D123V	0.995
5:33998660:G:C	F240L	0.992
5:33998660:G:T	F240L	0.992
5:33998662:A:G	F240L	0.992
5:33989395:A:G	W283R	0.990
5:33989395:A:T	W283R	0.990
5:34005772:G:C	N125K	0.990
5:34005772:G:T	N125K	0.990
5:34005817:A:C	F110L	0.989
5:34005817:A:T	F110L	0.989
5:34005819:A:G	F110L	0.989
5:33989363:A:C	C293W	0.988
5:34005779:T:G	D123A	0.988
5:33989352:A:T	V297D	0.987
5:34004671:T:A	D152V	0.987
5:33998682:A:T	V233D	0.986
5:34004670:G:C	D152E	0.986
5:34004670:G:T	D152E	0.986
5:33998723:G:C	F219L	0.984
5:33998723:G:T	F219L	0.984
5:33998725:A:G	F219L	0.984
5:34005780:C:A	D123Y	0.984
5:34005833:G:T	A105D	0.984
5:33998686:C:G	A232P	0.983
5:34007960:A:C	C20W	0.983
5:34004672:C:G	D152H	0.982
5:33989364:C:T	C293Y	0.981
5:34004682:A:C	N148K	0.981
5:34004682:A:T	N148K	0.981
5:34007870:C:A	K50N	0.981

dbSNP variants (sampled 300 via entrez): RS1000031820 (5:34008997 C>T), RS1000318523 (5:33992939 T>C), RS1000419316 (5:33986346 T>G), RS1000516996 (5:33991899 G>A), RS1000649277 (5:33992647 C>T), RS1000843834 (5:34004713 C>T), RS1001009756 (5:33998349 A>T), RS1001054722 (5:33991695 A>G), RS1001093562 (5:33997859 C>A), RS1001211002 (5:33985935 C>A), RS1001244657 (5:34008652 G>C), RS1001276130 (5:34005247 T>C), RS1001358237 (5:33989849 C>A), RS1001380536 (5:34008495 TTAGC>T,TTAGCTAGC), RS1001610655 (5:33998870 T>C)

Disease associations

OMIM: gene MIM:604489 | disease phenotypes: MIM:108600, MIM:614307, MIM:214950

GenCC curated gene-disease

Disease	Classification	Inheritance
alpha-methylacyl-CoA racemase deficiency	Definitive	Autosomal recessive
congenital bile acid synthesis defect 4	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
alpha-methylacyl-CoA racemase deficiency	Definitive	AR

Mondo (4): spastic ataxia (MONDO:0017845), alpha-methylacyl-CoA racemase deficiency (MONDO:0013681), congenital bile acid synthesis defect 4 (MONDO:0008967), primary ovarian failure (MONDO:0005387)

Orphanet (3): Spastic ataxia (Orphanet:316226), Congenital bile acid synthesis defect type 4 (Orphanet:79095), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0000580	Pigmentary retinopathy
HP:0000716	Depression
HP:0000763	Sensory neuropathy
HP:0000815	Hypergonadotropic hypogonadism
HP:0001081	Cholelithiasis
HP:0001133	Constriction of peripheral visual field
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001269	Hemiparesis
HP:0001298	Encephalopathy
HP:0001328	Specific learning disability
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001392	Abnormality of the liver
HP:0001399	Hepatic failure
HP:0001406	Intrahepatic cholestasis
HP:0001508	Failure to thrive
HP:0002076	Migraine
HP:0002080	Intention tremor
HP:0002133	Status epilepticus
HP:0002240	Hepatomegaly
HP:0002354	Memory impairment

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007344_21	Estimated glomerular filtration rate	7.000000e-11

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C565768	Alpha-Methylacyl-CoA Racemase Deficiency (supp.)
C535444	Bile acid synthesis defect, congenital, 4 (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, affects expression, decreases expression, increases expression	4
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Ibuprofen	increases activity, increases metabolic processing, affects response to substance	2
Testosterone	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
bisphenol F	increases methylation, affects cotreatment	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
bleomycetin	decreases expression	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
1-methylphenanthrene	affects cotreatment, affects expression	1
dibenzo(a,l)pyrene	affects cotreatment, affects expression	1
bicalutamide	decreases expression	1
pterostilbene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Silybin	decreases expression	1
Acetylcysteine	affects expression, decreases reaction	1
Amphotericin B	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure