EHHADH

Summary

EHHADH (enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase, HGNC:3247) is a protein-coding gene on chromosome 3q27.2, encoding Peroxisomal bifunctional enzyme (Q08426). Peroxisomal trifunctional enzyme possessing 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and delta 3, delta 2-enoyl-CoA isomerase activities.

The protein encoded by this gene is a bifunctional enzyme and is one of the four enzymes of the peroxisomal beta-oxidation pathway. The N-terminal region of the encoded protein contains enoyl-CoA hydratase activity while the C-terminal region contains 3-hydroxyacyl-CoA dehydrogenase activity. Defects in this gene are a cause of peroxisomal disorders such as Zellweger syndrome. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1962 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi renotubular syndrome 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 279 total
• Phenotypes (HPO): 39
• MANE Select transcript: NM_001966

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3247
Approved symbol	EHHADH
Name	enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase
Location	3q27.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113790
Ensembl biotype	protein_coding
OMIM	607037
Entrez	1962

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000231887, ENST00000440662, ENST00000456310, ENST00000465178, ENST00000475987, ENST00000483104, ENST00000890153, ENST00000890154, ENST00000890155

RefSeq mRNA: 2 — MANE Select: NM_001966 NM_001166415, NM_001966

CCDS: CCDS33901, CCDS54694

Canonical transcript exons

ENST00000231887 — 7 exons

Exon	Start	End
ENSE00000781366	185204416	185204757
ENSE00000871360	185190624	185193487
ENSE00000871361	185218136	185218240
ENSE00001836125	185253949	185254049
ENSE00003524064	185248414	185248517
ENSE00003573672	185229432	185229543
ENSE00003670116	185235290	185235462

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 96.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.3453 / max 194.1494, expressed in 1272 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45914	2.7576	1149
45915	0.5877	302

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.98	gold quality
liver	UBERON:0002107	96.46	gold quality
nephron tubule	UBERON:0001231	95.39	gold quality
kidney epithelium	UBERON:0004819	92.11	gold quality
adult mammalian kidney	UBERON:0000082	91.93	gold quality
kidney	UBERON:0002113	90.92	gold quality
jejunal mucosa	UBERON:0000399	89.28	gold quality
renal glomerulus	UBERON:0000074	88.69	gold quality
cortex of kidney	UBERON:0001225	88.39	gold quality
metanephric glomerulus	UBERON:0004736	87.95	gold quality
renal medulla	UBERON:0000362	87.66	gold quality
esophagus squamous epithelium	UBERON:0006920	86.66	gold quality
choroid plexus epithelium	UBERON:0003911	86.45	gold quality
mucosa of transverse colon	UBERON:0004991	85.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.07	gold quality
metanephros	UBERON:0000081	84.25	gold quality
rectum	UBERON:0001052	82.86	gold quality
duodenum	UBERON:0002114	82.76	gold quality
epithelium of esophagus	UBERON:0001976	82.60	gold quality
pigmented layer of retina	UBERON:0001782	82.25	gold quality
metanephros cortex	UBERON:0010533	82.10	gold quality
islet of Langerhans	UBERON:0000006	81.55	gold quality
mucosa of paranasal sinus	UBERON:0005030	79.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.24	gold quality
colonic mucosa	UBERON:0000317	79.23	gold quality
heart left ventricle	UBERON:0002084	77.88	gold quality
transverse colon	UBERON:0001157	77.70	gold quality
cardiac ventricle	UBERON:0002082	77.56	gold quality
pancreas	UBERON:0001264	77.38	gold quality
parietal pleura	UBERON:0002400	77.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-10	no	419.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, PPARA

miRNA regulators (miRDB)

113 targeting EHHADH, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 4)

• Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi’s syndrome; this indicates a central role of mitochondria in proximal tubular function. (PMID:24401050)
• EHHADH contributes to cisplatin resistance through regulation by tumor-suppressive microRNAs in bladder cancer. (PMID:33430801)
• [EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis]. (PMID:37313808)
• Positive regulation of cell proliferation by the miR-1290-EHHADH axis in hepatocellular carcinoma. (PMID:38498379)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ehhadh	ENSDARG00000070029
mus_musculus	Ehhadh	ENSMUSG00000022853
rattus_norvegicus	Ehhadh	ENSRNOG00000001770
caenorhabditis_elegans		WBGENE00001157
caenorhabditis_elegans		WBGENE00001158

Paralogs (3): HADHA (ENSG00000084754), HADH (ENSG00000138796), CRYL1 (ENSG00000165475)

Protein

Protein identifiers

Peroxisomal bifunctional enzyme — Q08426 (reviewed: Q08426)

Alternative names: L-bifunctional protein, Multifunctional enzyme 1

All UniProt accessions (2): C9JJE0, Q08426

UniProt curated annotations — full annotation on UniProt →

Function. Peroxisomal trifunctional enzyme possessing 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and delta 3, delta 2-enoyl-CoA isomerase activities. Catalyzes two of the four reactions of the long chain fatty acids peroxisomal beta-oxidation pathway. Can also use branched-chain fatty acids such as 2-methyl-2E-butenoyl-CoA as a substrate, which is hydrated into (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA. Optimal isomerase for 2,5 double bonds into 3,5 form isomerization in a range of enoyl-CoA species. Also able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species. With HSD17B4, catalyzes the hydration of trans-2-enoyl-CoA and the dehydrogenation of 3-hydroxyacyl-CoA, but with opposite chiral specificity. Regulates the amount of medium-chain dicarboxylic fatty acids which are essential regulators of all fatty acid oxidation pathways. Also involved in the degradation of long-chain dicarboxylic acids through peroxisomal beta-oxidation.

Subunit / interactions. Monomer.

Subcellular location. Peroxisome.

Tissue specificity. Liver and kidney. Strongly expressed in the terminal segments of the proximal tubule. Lower amounts seen in the brain.

Post-translational modifications. Acetylated, leading to enhanced enzyme activity. Acetylation is enhanced by up to 80% after treatment either with trichostin A (TSA) or with nicotinamide (NAM) with highest increase on Lys-346. Acetylation and enzyme activity increased by about 1.5% on addition of fatty acids.

Disease relevance. Fanconi renotubular syndrome 3 (FRTS3) [MIM:615605] A form of Fanconi renotubular syndrome, a disease due to a generalized dysfunction of the proximal kidney tubule resulting in decreased solute and water reabsorption. Patients have polydipsia and polyuria with phosphaturia, glycosuria and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, acidosis and a tendency toward dehydration. Some eventually develop renal insufficiency. FRTS3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Enzyme activity enhanced by acetylation.

Pathway. Lipid metabolism; fatty acid beta-oxidation.

Miscellaneous. Absent in patients suffering with peroxisomal disorders such as Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease.

Similarity. In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family. In the C-terminal section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q08426-1	1	yes
Q08426-2	2

RefSeq proteins (2): NP_001159887, NP_001957* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001753	Enoyl-CoA_hydra/iso	Domain
IPR006108	3HC_DH_C	Domain
IPR006176	3-OHacyl-CoA_DH_NAD-bd	Domain
IPR006180	3-OHacyl-CoA_DH_CS	Conserved_site
IPR008927	6-PGluconate_DH-like_C_sf	Homologous_superfamily
IPR018376	Enoyl-CoA_hyd/isom_CS	Conserved_site
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00378, PF00725, PF02737

Catalyzed reactions (Rhea), 12 shown:

• a (3S)-3-hydroxyacyl-CoA = a (2E)-enoyl-CoA + H2O (RHEA:16105)
• a 4-saturated-(3S)-3-hydroxyacyl-CoA = a (3E)-enoyl-CoA + H2O (RHEA:20724)
• a (3S)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH + H(+) (RHEA:22432)
• (3S)-hydroxyhexanoyl-CoA = (2E)-hexenoyl-CoA + H2O (RHEA:30547)
• (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA = (2E)-2-methylbut-2-enoyl-CoA + H2O (RHEA:31119)
• (3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA + NADH + H(+) (RHEA:31159)
• (3S)-hydroxyhexadecanoyl-CoA = (2E)-hexadecenoyl-CoA + H2O (RHEA:31163)
• (3S)-hydroxydecanoyl-CoA + NAD(+) = 3-oxodecanoyl-CoA + NADH + H(+) (RHEA:31187)
• (3S)-hydroxydecanoyl-CoA = (2E)-decenoyl-CoA + H2O (RHEA:31191)
• (2E)-hexadecenedioyl-CoA + H2O = (3S)-hydroxyhexadecanedioyl-CoA (RHEA:40259)
• (3S)-hydroxyhexadecanedioyl-CoA + NAD(+) = 3-oxohexadecanedioyl-CoA + NADH + H(+) (RHEA:40267)
• a (3E)-enoyl-CoA = a 4-saturated (2E)-enoyl-CoA (RHEA:45228)

UniProt features (47 total): modified residue 23, sequence variant 10, mutagenesis site 4, region of interest 2, sequence conflict 2, site 2, chain 1, short sequence motif 1, splice variant 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08426-F1	95.07	0.93

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): 104 (important for catalytic activity); 124 (important for catalytic activity)

Ligand- & substrate-binding residues (1): 101

Post-translational modifications (23): 171, 219, 219, 250, 280, 290, 346, 350, 464, 532, 548, 577, 584, 584, 591, 591, 710, 710, 718, 722 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
165	greatly reduced acetylation and insensitive to treatment with tsa and nam; when associated with q-171; q-346 and q-584.
171	greatly reduced acetylation and insensitive to treatment with tsa and nam; when associated with q-165; q-346 and q-584.
346	greatly reduced acetylation and insensitive to treatment with tsa and nam; when associated with q-165; q-171 and q-584.
584	greatly reduced acetylation and insensitive to treatment with tsa and nam; when associated with q-165; q-171 and q-346.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390247	Beta-oxidation of very long chain fatty acids
R-HSA-9033241	Peroxisomal protein import

MSigDB gene sets: 296 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, BOYLAN_MULTIPLE_MYELOMA_D_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, SMITH_TERT_TARGETS_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_OXIDASE, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, KEGG_PPAR_SIGNALING_PATHWAY, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_FATTY_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (8): fatty acid beta-oxidation (GO:0006635), unsaturated fatty acid biosynthetic process (GO:0006636), fatty acid beta-oxidation using acyl-CoA oxidase (GO:0033540), alpha-linolenic acid metabolic process (GO:0036109), long-chain fatty acid biosynthetic process (GO:0042759), fatty acid derivative biosynthetic process (GO:1901570), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (14): (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity (GO:0003857), delta(3)-delta(2)-enoyl-CoA isomerase activity (GO:0004165), enoyl-CoA hydratase activity (GO:0004300), long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity (GO:0016509), intramolecular oxidoreductase activity, transposing C=C bonds (GO:0016863), 3-hydroxyacyl-CoA dehydratase activity (GO:0018812), enzyme binding (GO:0019899), NAD+ binding (GO:0070403), catalytic activity (GO:0003824), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), lyase activity (GO:0016829), isomerase activity (GO:0016853)

GO Cellular Component (3): peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peroxisomal lipid metabolism	1
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	3
fatty acid biosynthetic process	2
unsaturated fatty acid metabolic process	2
long-chain fatty acid metabolic process	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
fatty acid beta-oxidation	1
olefinic compound metabolic process	1
lipid biosynthetic process	1
fatty acid derivative metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
intramolecular oxidoreductase activity, transposing C=C bonds	1
hydro-lyase activity	1
(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity	1
intramolecular oxidoreductase activity	1
enoyl-CoA hydratase activity	1
protein binding	1
anion binding	1
NAD binding	1
molecular_function	1
binding	1
oxidoreductase activity, acting on CH-OH group of donors	1
microbody	1
peroxisome	1
microbody lumen	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2693 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EHHADH	HADHB	P55084	971
EHHADH	ACOX1	Q15067	968
EHHADH	HSD17B4	P51659	966
EHHADH	ACAA1	P09110	939
EHHADH	ACOX3	O15254	885
EHHADH	ACAA2	P42765	883
EHHADH	ACOX2	Q99424	821
EHHADH	PPARA	Q07869	757
EHHADH	PEX10	O60683	717
EHHADH	GNPAT	O15228	683
EHHADH	ACACB	O00763	681
EHHADH	ACOT4	Q8N9L9	667
EHHADH	ACADM	P11310	660
EHHADH	PEX5	P50542	648
EHHADH	ACSL1	P33121	644

IntAct

414 interactions, top by confidence:

A	B	Type	Score
EHHADH	TRIM41	psi-mi:“MI:0915”(physical association)	0.870
TRIM41	EHHADH	psi-mi:“MI:0915”(physical association)	0.870
MID1	EHHADH	psi-mi:“MI:0915”(physical association)	0.780
EHHADH	MID1	psi-mi:“MI:0915”(physical association)	0.780
KCTD6	EHHADH	psi-mi:“MI:0915”(physical association)	0.740
EHHADH	KCTD6	psi-mi:“MI:0915”(physical association)	0.740
TRIM27	EHHADH	psi-mi:“MI:0915”(physical association)	0.720
DES	EHHADH	psi-mi:“MI:0915”(physical association)	0.720
EHHADH	ZBTB9	psi-mi:“MI:0915”(physical association)	0.720
ZBTB9	EHHADH	psi-mi:“MI:0915”(physical association)	0.720
CCDC102B	EHHADH	psi-mi:“MI:0915”(physical association)	0.670
SSNA1	EHHADH	psi-mi:“MI:0915”(physical association)	0.670
TPP2	EHHADH	psi-mi:“MI:0915”(physical association)	0.670
EHHADH	CBS	psi-mi:“MI:0915”(physical association)	0.670
EHHADH	ACTG1	psi-mi:“MI:0915”(physical association)	0.670
EHHADH	TNIP1	psi-mi:“MI:0915”(physical association)	0.670
EHHADH	KCTD9	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (174): EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), MID1 (Two-hybrid), TRIM27 (Two-hybrid), TPP2 (Two-hybrid), TRAF1 (Two-hybrid), BHLHE40 (Two-hybrid), SSNA1 (Two-hybrid), PNMA1 (Two-hybrid), TNIP1 (Two-hybrid), NECAB2 (Two-hybrid)

ESM2 similar proteins: B3DMA2, O62138, O64894, O65201, O65202, O75891, P0C2X9, P0CZ23, P12007, P15650, P26440, P28037, P28330, P34275, P51174, P54886, P54889, P55100, P70584, P79274, P97562, Q08426, Q15067, Q3SY69, Q3SZI8, Q3SZP5, Q50LG2, Q5R4M8, Q5R5M8, Q5R778, Q5RBD5, Q5RC19, Q5RFM9, Q5ZHT1, Q60HI0, Q6JQN1, Q709F0, Q80XL6, Q8HYL8, Q8K009

Diamond homologs: A0KEL1, A0KR50, A0QJH8, A1JIG4, A1JK30, A1KN36, A1S1I8, A1S7L6, A4STF2, A4YI89, A5U753, A5W6H0, A5WH99, A6V382, A7FGK1, A7MH81, A7MQP0, A8A2L0, A8ACZ4, A8ALR7, A8GH86, A8GYG0, A9MR28, B0KH74, B1J5A5, B1KCZ3, B1LME7, B6EGU2, B7NP24, B7UYR6, C3K613, C6DAL7, F1LU71, F4JML5, O07137, O34893, O49809, P07896, P0ABU0, P0ABU1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	176
Likely benign	33
Benign	31

Top pathogenic / likely-pathogenic (0)

SpliceAI

1103 predictions. Top by Δscore:

Variant	Effect	Δscore
3:185218130:TCTTA:T	donor_loss	1.0000
3:185218131:CTTA:C	donor_loss	1.0000
3:185218132:TTACC:T	donor_loss	1.0000
3:185218133:TACCT:T	donor_loss	1.0000
3:185218134:A:C	donor_loss	1.0000
3:185218135:CCTG:C	donor_loss	1.0000
3:185235289:CCT:C	donor_gain	1.0000
3:185235462:CCTAA:C	acceptor_loss	1.0000
3:185235463:C:CA	acceptor_loss	1.0000
3:185248518:C:CC	acceptor_gain	1.0000
3:185253943:CGTTA:C	donor_loss	1.0000
3:185253944:GTTAC:G	donor_loss	1.0000
3:185253945:TTACC:T	donor_loss	1.0000
3:185253946:TA:T	donor_loss	1.0000
3:185253947:A:C	donor_loss	1.0000
3:185253948:CC:C	donor_loss	1.0000
3:185204757:TCTG:T	acceptor_loss	0.9900
3:185204759:T:G	acceptor_loss	0.9900
3:185218237:CTTC:C	acceptor_gain	0.9900
3:185218238:TTC:T	acceptor_gain	0.9900
3:185218241:C:CC	acceptor_gain	0.9900
3:185218241:CT:C	acceptor_loss	0.9900
3:185218242:T:A	acceptor_loss	0.9900
3:185229427:CTGA:C	donor_loss	0.9900
3:185229428:TGA:T	donor_loss	0.9900
3:185229429:GACC:G	donor_loss	0.9900
3:185229431:C:A	donor_loss	0.9900
3:185229544:C:CG	acceptor_loss	0.9900
3:185229545:T:G	acceptor_loss	0.9900
3:185235287:TACCT:T	donor_loss	0.9900

AlphaMissense

4663 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:185193231:C:A	K389N	0.996
3:185193231:C:G	K389N	0.996
3:185192432:A:G	W656R	0.995
3:185192432:A:T	W656R	0.995
3:185192961:A:C	F479L	0.995
3:185192961:A:T	F479L	0.995
3:185192963:A:G	F479L	0.995
3:185192950:C:G	R483P	0.994
3:185193096:A:C	F434L	0.993
3:185193096:A:T	F434L	0.993
3:185193098:A:G	F434L	0.993
3:185193171:A:C	N409K	0.993
3:185193171:A:T	N409K	0.993
3:185193179:A:G	C407R	0.992
3:185193099:G:C	F433L	0.990
3:185193099:G:T	F433L	0.990
3:185193101:A:G	F433L	0.990
3:185192459:C:G	D647H	0.989
3:185193104:G:C	H432D	0.989
3:185192413:C:T	G662E	0.988
3:185204485:A:G	W281R	0.988
3:185204485:A:T	W281R	0.988
3:185204421:A:T	V302D	0.987
3:185192459:C:A	D647Y	0.985
3:185193173:T:A	N409Y	0.985
3:185193265:A:T	V378D	0.985
3:185235305:C:A	R112S	0.985
3:185235305:C:G	R112S	0.985
3:185192663:A:G	W579R	0.984
3:185192663:A:T	W579R	0.984

dbSNP variants (sampled 300 via entrez): RS1000035855 (3:185198930 G>A,C), RS1000084392 (3:185254523 A>G), RS1000084548 (3:185228418 C>T), RS1000362049 (3:185219976 G>A,C,T), RS1000530105 (3:185226800 A>G), RS1000533085 (3:185254930 T>G), RS1000549915 (3:185241938 A>G), RS1000560853 (3:185228701 C>A,G), RS1000606296 (3:185234859 G>A), RS1000616053 (3:185234655 T>C), RS1000698332 (3:185212698 T>C), RS1000707464 (3:185249869 G>A), RS1000831837 (3:185193675 T>A,C), RS1000940561 (3:185200438 T>C), RS1000940916 (3:185248734 C>A)

Disease associations

OMIM: gene MIM:607037 | disease phenotypes: MIM:615605, MIM:134600

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi renotubular syndrome 3	Strong	Autosomal dominant
primary Fanconi syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Fanconi renotubular syndrome 3	Limited	AD

Mondo (5): Fanconi renotubular syndrome 3 (MONDO:0014275), Fanconi renotubular syndrome 1 (MONDO:0024525), chronic kidney disease (MONDO:0005300), cholestasis (MONDO:0001751), primary Fanconi syndrome (MONDO:0007600)

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000117	Renal phosphate wasting
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001824	Weight loss
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0002049	Proximal renal tubular acidosis
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002206	Pulmonary fibrosis
HP:0002653	Bone pain
HP:0002659	Increased susceptibility to fractures
HP:0002748	Rickets
HP:0002749	Osteomalacia
HP:0002900	Hypokalemia
HP:0002909	Generalized aminoaciduria
HP:0002979	Bowing of the legs
HP:0003076	Glycosuria
HP:0003081	Increased urinary potassium
HP:0003109	Hyperphosphaturia
HP:0003126	Low-molecular-weight proteinuria
HP:0003149	Hyperuricosuria
HP:0003234	Decreased circulating carnitine concentration
HP:0003259	Elevated circulating creatinine concentration
HP:0003355	Aminoaciduria
HP:0003537	Hypouricemia
HP:0003593	Infantile onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000477_21	Cognitive performance	2.000000e-06
GCST000856_3	Major depressive disorder	5.000000e-06
GCST003558_1	Major depressive disorder	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002779	Cholestasis	C06.130.120.135
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	5
Cyclosporine	decreases expression	5
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, affects methylation	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
nickel sulfate	increases expression	2
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
fluorotelomer sulfonic acids	increases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects expression	1
chlortoluron	decreases expression	1
nuciferine	decreases expression, decreases reaction, increases reaction	1
trichostatin A	increases expression	1
dioctyl adipate	increases expression, affects response to substance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases reaction, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
periodate-oxidized adenosine	affects expression	1
1-nitropyrene	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)
NCT00958451	PHASE4	COMPLETED	Vitamin D Deficiency in Chronic Kidney Disease (CKD) Patients