FA2H

Summary

FA2H (fatty acid 2-hydroxylase, HGNC:21197) is a protein-coding gene on chromosome 16q23.1, encoding Fatty acid 2-hydroxylase (Q7L5A8). Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.

This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.

Source: NCBI Gene 79152 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 35 (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 432 total — 33 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_024306

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21197
Approved symbol	FA2H
Name	fatty acid 2-hydroxylase
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FAAH, FLJ25287
Ensembl gene	ENSG00000103089
Ensembl biotype	protein_coding
OMIM	611026
Entrez	79152

Gene structure

Transcript identifiers

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

ENST00000219368, ENST00000562145, ENST00000567683, ENST00000569949, ENST00000618933, ENST00000888351, ENST00000888352

RefSeq mRNA: 1 — MANE Select: NM_024306 NM_024306

CCDS: CCDS10911

Canonical transcript exons

ENST00000219368 — 7 exons

Exon	Start	End
ENSE00000694682	74727244	74727386
ENSE00000694686	74726225	74726331
ENSE00002605898	74774486	74774820
ENSE00003567408	74740023	74740115
ENSE00003590273	74712969	74714269
ENSE00003628879	74716347	74716599
ENSE00003641043	74718988	74719160

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.32.

FANTOM5 (CAGE): breadth broad, TPM avg 8.1471 / max 603.2279, expressed in 576 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158131	3.6595	509
158130	3.5499	335
158128	0.6656	197
158126	0.1845	68
158129	0.0453	22
158127	0.0423	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.32	gold quality
spinal cord	UBERON:0002240	97.95	gold quality
corpus callosum	UBERON:0002336	96.04	gold quality
inferior olivary complex	UBERON:0002127	95.92	gold quality
inferior vagus X ganglion	UBERON:0005363	95.91	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.20	gold quality
cranial nerve II	UBERON:0000941	94.12	gold quality
olfactory bulb	UBERON:0002264	93.88	silver quality
medulla oblongata	UBERON:0001896	93.34	gold quality
subthalamic nucleus	UBERON:0001906	91.83	gold quality
sural nerve	UBERON:0015488	91.65	gold quality
substantia nigra	UBERON:0002038	91.48	gold quality
midbrain	UBERON:0001891	91.44	gold quality
pons	UBERON:0000988	90.84	silver quality
mucosa of transverse colon	UBERON:0004991	90.79	gold quality
tibial nerve	UBERON:0001323	90.59	gold quality
superior vestibular nucleus	UBERON:0007227	90.45	silver quality
ventral tegmental area	UBERON:0002691	89.97	gold quality
Ammon’s horn	UBERON:0001954	89.42	gold quality
CA1 field of hippocampus	UBERON:0003881	89.06	silver quality
endothelial cell	CL:0000115	89.04	gold quality
colonic mucosa	UBERON:0000317	88.83	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.70	silver quality
putamen	UBERON:0001874	88.64	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.41	silver quality
mucosa of sigmoid colon	UBERON:0004993	87.94	gold quality
upper leg skin	UBERON:0004262	87.58	gold quality
postcentral gyrus	UBERON:0002581	87.57	gold quality
amygdala	UBERON:0001876	86.92	gold quality
parietal lobe	UBERON:0001872	86.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

94 targeting FA2H, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-659-3P	99.85	70.69	1620

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• the human FA2H gene encodes a fatty acid 2-hydroxylase involved in the formation of myelin 2-hydroxy galactosylceramides and -sulfatides (PMID:15337768)
• late differentiation-linked increases in FA2H expression are essential for epidermal permeability barrier homeostasis. (PMID:17355976)
• Mutations in FA2H are associated with leukodystrophy with spastic paraparesis and dystonia. (PMID:19068277)
• Mutations in FA2H are associated with hereditary spastic paraplegia. (PMID:20104589)
• a novel homozygous c.270+3A>T mutation altered FA2H function led to a severe phenotype, with clinical features overlapping those in three FA2H-associated disorders (PMID:21592092)
• The 2-hydroxylated sphingomyelin (SM) profiles were characterized in blood and fibroblasts from patients harboring a deleterious FA2H mutation. (PMID:21599921)
• This study did not find any mutations in the FA2H gene in patients with neurodegeneration with brain iron accumulation. (PMID:22704260)
• we report a novel mutation in FA2H gene in two sibs presenting with adult onset complicated spastic paraparesis and thin corpus callosum (PMID:22925154)
• FA2H is a novel (9)-THC-regulated gene, and that (9)-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells. (PMID:23535410)
• Identification of a novel triple heterozygous mutations in FA2H gene (c.968C>A; c.976G>A; c.688G>A) in a Chinese family with Hereditary Spastic Paraplegia Type 35. (PMID:23566484)
• One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. (PMID:24299421)
• Three novel mutations in Chinese patients significantly reduce FA2H enzyme activity leading to hereditary spastic paraplegia. (PMID:24359114)
• Induced levels of PPARalpha may be involved in the Delta(9)-THC up-regulation of FA2H in MDA-MB-231 cells. (PMID:25291031)
• Novel mutations in FA2H in Arab patients with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis were identified. (PMID:25496456)
• Study reports the clinical, neuroimaging, biochemical, and molecular findings in three novel unrelated patients with new mutations in FA2H, comparing their features with those previously reported in autosomal recessive spastic paraplegia 35 (SPG35). (PMID:29423566)
• PGRMC1 may regulate FA2H activity, possibly through its heme chaperone activity. (PMID:29438993)
• Novel variant c.130C>T (p.Pro44Ser) in homozygous status in exon 1 of the FA2H gene is described in a Czech patient with SPG35. (PMID:30446360)
• Hereditary spastic paraplegia type 35 caused by the FA2H mutation in a family from Mali has been described. (PMID:31087769)
• High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma (PMID:31409741)
• Fatty acid 2-hydroxylase (FA2H) as a stimulatory molecule responsible for breast cancer cell migration. (PMID:32798015)
• Overexpression of Fatty Acid 2-Hydroxylase is Associated with an Increased Sensitivity to Cisplatin by Ovarian Cancer and Better Prognoses. (PMID:33064010)
• 2-Hydroxylation of Fatty Acids Represses Colorectal Tumorigenesis and Metastasis via the YAP Transcriptional Axis. (PMID:33203703)
• Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H. (PMID:33246395)
• Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases. (PMID:36902339)
• The first reports of FA2H-associated neurodegeneration from two unrelated Iranian families. (PMID:37410270)
• A Novel Homozygous Deletion Including Exon 1 of FA2H Gene Causes Spastic Paraplegia-35: Genetic and Lipidomics Analysis of the Patients. (PMID:38306901)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fa2h	ENSDARG00000090063
mus_musculus	Fa2h	ENSMUSG00000033579
rattus_norvegicus	Fa2h	ENSRNOG00000018950
drosophila_melanogaster	Fa2h	FBGN0050502
caenorhabditis_elegans	fath-1	WBGENE00007707

Protein

Protein identifiers

Fatty acid 2-hydroxylase — Q7L5A8 (reviewed: Q7L5A8)

Alternative names: Fatty acid alpha-hydroxylase, Fatty acid hydroxylase domain-containing protein 1

All UniProt accessions (4): Q7L5A8, A0A087WVM8, H3BP32, J3QS89

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis. FA2H is stereospecific for the production of (R)-2-hydroxy fatty acids. Plays an essential role in the synthesis of galactosphingolipids of the myelin sheath. Responsible for the synthesis of sphingolipids and glycosphingolipids involved in the formation of epidermal lamellar bodies critical for skin permeability barrier. Participates in the synthesis of glycosphingolipids and a fraction of type II wax diesters in sebaceous gland, specifically regulating hair follicle homeostasis. Involved in the synthesis of sphingolipids of plasma membrane rafts, controlling lipid raft mobility and trafficking of raft-associated proteins.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane.

Tissue specificity. Detected in differentiating cultured keratinocytes (at protein level). Detected in epidermis and cultured keratinocytes. Highly expressed in brain and colon. Detected at lower levels in testis, prostate, pancreas and kidney.

Disease relevance. Spastic paraplegia 35, autosomal recessive, with or without neurodegeneration (SPG35) [MIM:612319] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG35 is a complicated form characterized by childhood onset of gait difficulties. It has a rapid progression and many patients become wheelchair-bound as young adults. Patients manifest cognitive decline associated with leukodystrophy. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Zn(2+) ions per subunit that likely form a catalytic dimetal center.

Domain organisation. The histidine box domains may contain the active site and/or be involved in metal ion binding. The N-terminal cytochrome b5 heme-binding domain is essential for catalytic activity.

Induction. Up-regulated during keratinocyte differentiation.

Pathway. Lipid metabolism; fatty acid metabolism. Sphingolipid metabolism; galactosylceramide biosynthesis.

Similarity. Belongs to the sterol desaturase family. SCS7 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7L5A8-1	1	yes
Q7L5A8-2	2

RefSeq proteins (1): NP_077282* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001199	Cyt_B5-like_heme/steroid-bd	Domain
IPR006694	Fatty_acid_hydroxylase	Domain
IPR014430	Scs7	Family
IPR018506	Cyt_B5_heme-BS	Binding_site
IPR036400	Cyt_B5-like_heme/steroid_sf	Homologous_superfamily

Pfam: PF00173, PF04116

Enzyme classification (BRENDA):

• EC 1.14.18.6 — 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase (BRENDA: 7 organisms, 12 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 5 shown:

• hexadecanoate + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = (R)-2-hydroxyhexadecanoate + 2 Fe(III)-[cytochrome b5] + H2O (RHEA:38551)
• tetracosanoate + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = (R)-2-hydroxytetracosanoate + 2 Fe(III)-[cytochrome b5] + H2O (RHEA:38559)
• a 1,2-saturated fatty acid + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = a (R)-2-hydroxy fatty acid + 2 Fe(III)-[cytochrome b5] + H2O (RHEA:38855)
• octadecanoate + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = (R)-2-hydroxyoctadecanoate + 2 Fe(III)-[cytochrome b5] + H2O (RHEA:39815)
• docosanoate + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = 2-hydroxydocosanoate + 2 Fe(III)-[cytochrome b5] + H2O (RHEA:39819)

UniProt features (27 total): binding site 12, sequence variant 5, transmembrane region 4, sequence conflict 2, domain 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L5A8-F1	85.53	0.67

Functional residue map

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

Ligand- & substrate-binding residues (12): 239; 257; 260; 261; 315; 319; 336; 339; 340; 43 (axial binding residue); 69 (axial binding residue); 234

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 531 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_LIPID_MODIFICATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GCANCTGNY_MYOD_Q6, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (18): sebaceous gland cell differentiation (GO:0001949), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), glucosylceramide biosynthetic process (GO:0006679), galactosylceramide biosynthetic process (GO:0006682), sphingolipid biosynthetic process (GO:0030148), lipid modification (GO:0030258), central nervous system myelin maintenance (GO:0032286), peripheral nervous system myelin maintenance (GO:0032287), regulation of hair cycle (GO:0042634), plasma membrane raft organization (GO:0044857), ceramide biosynthetic process (GO:0046513), establishment of skin barrier (GO:0061436), regulation of sebum secreting cell proliferation (GO:1904002), regulation of acinar cell proliferation (GO:1904697), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), lipid biosynthetic process (GO:0008610)

GO Molecular Function (8): iron ion binding (GO:0005506), heme binding (GO:0020037), fatty acid 2-hydroxylase activity (GO:0080132), free fatty acid 2-hydroxylase activity (GO:0120520), 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase activity (GO:0120521), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	4
lipid biosynthetic process	2
glycosphingolipid biosynthetic process	2
ceramide biosynthetic process	2
myelin maintenance	2
regulation of epithelial cell proliferation	2
fatty acid 2-hydroxylase activity	2
epidermal cell differentiation	1
sebaceous gland development	1
monocarboxylic acid metabolic process	1
fatty acid metabolic process	1
monocarboxylic acid biosynthetic process	1
glucosylceramide metabolic process	1
galactosylceramide metabolic process	1
galactolipid biosynthetic process	1
sphingolipid metabolic process	1
central nervous system myelination	1
myelination in peripheral nervous system	1
hair cycle	1
regulation of multicellular organismal process	1
plasma membrane organization	1
membrane raft organization	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
skin epidermis development	1
sebum secreting cell proliferation	1
acinar cell proliferation	1
primary metabolic process	1
biosynthetic process	1
transition metal ion binding	1
tetrapyrrole binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, another compound as one donor, and incorporation of one atom of oxygen	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1

Protein interactions and networks

STRING

1952 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FA2H	AGMO	Q6ZNB7	942
FA2H	C19orf12	Q9NSK7	853
FA2H	ALDH3A2	P51648	777
FA2H	PANK2	Q9BZ23	736
FA2H	DCAF17	Q5H9S7	719
FA2H	COASY	Q13057	716
FA2H	PLA2G6	O60733	670
FA2H	SPG7	Q9UQ90	668
FA2H	GBA2	Q9HCG7	653
FA2H	SPG11	Q96JI7	651
FA2H	ATP13A2	Q9NQ11	624
FA2H	SPG21	Q9NZD8	617
FA2H	DDHD2	O94830	617
FA2H	WDR45	Q9Y484	617
FA2H	PNPLA6	Q8IY17	611

IntAct

93 interactions, top by confidence:

A	B	Type	Score
FA2H	PGRMC2	psi-mi:“MI:0915”(physical association)	0.560
FA2H	ARMC12	psi-mi:“MI:0915”(physical association)	0.560
MSR1	FA2H	psi-mi:“MI:0915”(physical association)	0.560
DLG2	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
ASGR2	FA2H	psi-mi:“MI:0915”(physical association)	0.560
PGRMC2	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	TMX2	psi-mi:“MI:0915”(physical association)	0.560
FA2H	TMEM41A	psi-mi:“MI:0915”(physical association)	0.560
ARMC12	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	TLCD4	psi-mi:“MI:0915”(physical association)	0.560
SGPL1	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	GPX8	psi-mi:“MI:0915”(physical association)	0.560
FA2H	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
FA2H	GPR152	psi-mi:“MI:0915”(physical association)	0.560
EBP	FA2H	psi-mi:“MI:0915”(physical association)	0.560
PEX12	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	FA2H	psi-mi:“MI:0915”(physical association)	0.560
FA2H	RIC3	psi-mi:“MI:0915”(physical association)	0.560
FA2H	SYT2	psi-mi:“MI:0915”(physical association)	0.560
FA2H	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	FA2H	psi-mi:“MI:0915”(physical association)	0.560
ERLIN1	FA2H	psi-mi:“MI:0915”(physical association)	0.560
MARCHF8	FA2H	psi-mi:“MI:0915”(physical association)	0.560
AQP6	FA2H	psi-mi:“MI:0915”(physical association)	0.560
CD79A	FA2H	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (54): FA2H (Two-hybrid), FA2H (Proximity Label-MS), FA2H (Two-hybrid), FA2H (Two-hybrid), FA2H (Affinity Capture-MS), FA2H (Two-hybrid), FA2H (Two-hybrid), FA2H (Two-hybrid), CD79A (Two-hybrid), ERLIN1 (Two-hybrid), PEX12 (Two-hybrid), ELOVL4 (Two-hybrid), FAM209A (Two-hybrid), ERGIC3 (Two-hybrid), TMEM14B (Two-hybrid)

ESM2 similar proteins: A0JPQ8, A8MWK0, A9SIZ6, B6JWP7, C4QVU3, C4R613, D6WJ77, F1Q8R9, G5ECD6, I1MSF2, O13846, O17554, O31250, O74787, O94298, O94673, P21147, P25338, P68434, P9WNZ8, P9WNZ9, Q03529, Q296J9, Q2LAM0, Q2U0S9, Q4R4P4, Q567X1, Q5GKZ7, Q5M8F9, Q5MPP0, Q5R7H4, Q6GNM0, Q6NYE4, Q6RS96, Q6ZNB7, Q754G0, Q7L5A8, Q8BS35, Q8NKG9, Q8WZK2

Diamond homologs: A0A0C5PRW9, A0A286R227, A4FV48, A4IFP3, A4UVI1, A8MWK0, B2KKL4, B7GCG7, B8MKR3, B8R1K0, C8VJR5, D8X2C5, O04354, O22704, O43169, O48845, O60427, O74875, O94391, O95864, P00167, P00168, P00169, P00170, P00171, P00172, P00173, P00174, P00175, P04166, P07850, P08509, P08619, P09437, P11035, P11605, P11832, P16081, P17569, P17570

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	20
Uncertain significance	168
Likely benign	118
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073882	NM_024306.5(FA2H):c.21del (p.Ala8fs)	Pathogenic
1210342	NM_024306.5(FA2H):c.131del (p.Pro44fs)	Pathogenic
1373656	NM_024306.5(FA2H):c.1A>G (p.Met1Val)	Pathogenic
1435993	NM_024306.5(FA2H):c.240C>G (p.Tyr80Ter)	Pathogenic
1439740	NM_024306.5(FA2H):c.496A>T (p.Lys166Ter)	Pathogenic
1458952	NC_000016.9:g.(?74748088)(74808653_?)del	Pathogenic
1459206	NC_000016.9:g.(?74748068)(75513746_?)del	Pathogenic
1705931	NM_024306.5(FA2H):c.674T>C (p.Leu225Pro)	Pathogenic
1803968	NM_024306.5(FA2H):c.786G>A (p.Lys262=)	Pathogenic
1963059	NM_024306.5(FA2H):c.506G>A (p.Trp169Ter)	Pathogenic
208728	NM_024306.5(FA2H):c.565C>T (p.Arg189Ter)	Pathogenic
2137845	NM_024306.5(FA2H):c.265C>T (p.Gln89Ter)	Pathogenic
2149614	NM_024306.5(FA2H):c.888del (p.Gly298fs)	Pathogenic
2194147	NM_024306.5(FA2H):c.117C>G (p.Phe39Leu)	Pathogenic
241466	NM_024306.5(FA2H):c.821_822del (p.Pro274fs)	Pathogenic
242579	NC_000016.9:g.74808537G>T	Pathogenic
242580	NC_000016.9:g.74808495_74808504dupCCTGGCCCGC	Pathogenic
2426811	NC_000016.9:g.(?74808364)(74808653_?)del	Pathogenic
2637704	NM_024306.5(FA2H):c.911dup (p.Leu305fs)	Pathogenic
2715494	NM_024306.5(FA2H):c.865C>T (p.Gln289Ter)	Pathogenic
2873411	NM_024306.5(FA2H):c.162_171dup (p.Ile58fs)	Pathogenic
2907496	NM_024306.5(FA2H):c.503_506del (p.Val168fs)	Pathogenic
30871	NM_024306.5(FA2H):c.159_176del (p.Arg53_Ile58del)	Pathogenic
30873	NM_024306.5(FA2H):c.510_511del (p.Tyr170_Ser171delinsTer)	Pathogenic
31624	NM_024306.5(FA2H):c.707T>C (p.Phe236Ser)	Pathogenic
31625	NG_017070.1:g.(39810_52446)(66877?)del	Pathogenic
3381147	NM_024306.5(FA2H):c.893dup (p.Thr299fs)	Pathogenic
3776207	NM_024306.5(FA2H):c.581del (p.Gly194fs)	Pathogenic
458208	NC_000016.9:g.(?74750291)(74762108_?)del	Pathogenic
458306	NM_024306.5(FA2H):c.2T>C (p.Met1Thr)	Pathogenic

SpliceAI

4005 predictions. Top by Δscore:

Variant	Effect	Δscore
16:74716341:CCTCA:C	donor_loss	1.0000
16:74716342:CTCAC:C	donor_loss	1.0000
16:74716343:TCAC:T	donor_loss	1.0000
16:74716344:CA:C	donor_loss	1.0000
16:74716345:A:AG	donor_loss	1.0000
16:74716346:C:A	donor_loss	1.0000
16:74716346:CCTGA:C	donor_gain	1.0000
16:74718982:GCTCA:G	donor_loss	1.0000
16:74718983:CTCAC:C	donor_loss	1.0000
16:74718984:TCA:T	donor_loss	1.0000
16:74718985:CA:C	donor_loss	1.0000
16:74718986:ACC:A	donor_loss	1.0000
16:74718987:C:A	donor_loss	1.0000
16:74719157:TACT:T	acceptor_gain	1.0000
16:74719158:ACT:A	acceptor_gain	1.0000
16:74719159:CT:C	acceptor_gain	1.0000
16:74719159:CTC:C	acceptor_gain	1.0000
16:74719160:TC:T	acceptor_loss	1.0000
16:74719160:TCT:T	acceptor_gain	1.0000
16:74719161:C:CC	acceptor_gain	1.0000
16:74719161:CTG:C	acceptor_loss	1.0000
16:74719162:T:A	acceptor_loss	1.0000
16:74726219:CATTA:C	donor_loss	1.0000
16:74726220:ATTAC:A	donor_loss	1.0000
16:74726221:TTAC:T	donor_loss	1.0000
16:74726222:TAC:T	donor_loss	1.0000
16:74726223:ACCTG:A	donor_loss	1.0000
16:74726224:CCTGT:C	donor_loss	1.0000
16:74740018:GGTAC:G	donor_loss	1.0000
16:74740019:GTAC:G	donor_loss	1.0000

AlphaMissense

2428 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:74719012:G:C	F254L	0.997
16:74719012:G:T	F254L	0.997
16:74719014:A:G	F254L	0.997
16:74727318:C:A	W144C	0.996
16:74727318:C:G	W144C	0.996
16:74727320:A:G	W144R	0.996
16:74727320:A:T	W144R	0.996
16:74718988:C:A	K262N	0.995
16:74718988:C:G	K262N	0.995
16:74714256:G:C	S351R	0.993
16:74714256:G:T	S351R	0.993
16:74714258:T:G	S351R	0.993
16:74716443:G:C	H315D	0.993
16:74719070:C:G	R235P	0.992
16:74727282:G:C	F156L	0.992
16:74727282:G:T	F156L	0.992
16:74727284:A:G	F156L	0.992
16:74714265:A:C	F348L	0.991
16:74714265:A:T	F348L	0.991
16:74714267:A:G	F348L	0.991
16:74719060:G:C	F238L	0.991
16:74719060:G:T	F238L	0.991
16:74719062:A:G	F238L	0.991
16:74719074:G:C	H234D	0.991
16:74716441:A:C	H315Q	0.990
16:74716441:A:T	H315Q	0.990
16:74716581:G:T	R269S	0.990
16:74718996:G:C	H260D	0.990
16:74727245:A:G	W169R	0.990
16:74727245:A:T	W169R	0.990

dbSNP variants (sampled 300 via entrez): RS1000012099 (16:74763649 T>C), RS1000103989 (16:74713805 G>A), RS1000130119 (16:74727581 G>A), RS1000148904 (16:74729436 A>G), RS1000174776 (16:74715056 T>G), RS1000206718 (16:74769542 G>A), RS1000262601 (16:74734883 A>G), RS1000310026 (16:74748163 G>A), RS1000345834 (16:74759167 G>A), RS1000356328 (16:74753688 C>A,T), RS1000376374 (16:74729726 G>A,T), RS1000399638 (16:74759559 T>A), RS1000473785 (16:74717635 T>C), RS1000489525 (16:74753207 CAA>C,CA), RS1000502654 (16:74732316 G>A)

Disease associations

OMIM: gene MIM:611026 | disease phenotypes: MIM:612319, MIM:303350, MIM:217800, MIM:234200, MIM:108600

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 35	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary spastic paraplegia 35	Definitive	AR

Mondo (7): hereditary spastic paraplegia 35 (MONDO:0012866), hereditary spastic paraplegia (MONDO:0019064), macular corneal dystrophy (MONDO:0009020), intellectual disability (MONDO:0001071), neurodegeneration with brain iron accumulation (MONDO:0018307), neurodevelopmental disorder (MONDO:0700092), spastic ataxia (MONDO:0017845)

Orphanet (6): Autosomal recessive spastic paraplegia type 35 (Orphanet:171629), Hereditary spastic paraplegia (Orphanet:685), Macular corneal dystrophy (Orphanet:98969), Neurodegeneration with brain iron accumulation (Orphanet:385), Spastic ataxia (Orphanet:316226), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000298	Mask-like facies
HP:0000467	Neck muscle weakness
HP:0000486	Strabismus
HP:0000544	External ophthalmoplegia
HP:0000602	Ophthalmoplegia
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001123	Visual field defect
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002553_10	Pancreatic cancer	1.000000e-10
GCST002694_2	General cognitive ability	1.000000e-06
GCST003152_4	White matter lesion progression (adjusted for white matter lesion burden at baseline)	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0007746	white matter lesion progression measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C567311	Leukodystrophy, Dysmyelinating, And Spastic Paraparesis With Or Without Dystonia (supp.)
C537834	Macular dystrophy, corneal type 1 (supp.)
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879483 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dronabinol	decreases reaction, increases expression, increases reaction	3
MK-886	increases reaction, decreases reaction, increases expression	2
entinostat	increases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, decreases response to substance	2
Methotrexate	decreases expression, increases expression	2
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases reaction, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
pentanal	increases expression	1
GW 7647	increases expression	1
2-chloro-5-nitrobenzanilide	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dimethylarsinous acid	increases expression	1
5-chloro-1-(4-chlorobenzyl)-3-(phenylthio)indole-2-carboxylic acid	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
GSK0660	increases expression, increases reaction	1
NSC 689534	affects binding, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Aldehydes	increases expression	1
Atrazine	increases expression	1
Copper	affects binding, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4832176	Binding	Inhibition of human recombinant FAAH using AMC arachidonoyl amyl as substrate by fluorescence based assay	Monoacylglycerol lipase (MAGL) inhibitors based on a diphenylsulfide-benzoylpiperidine scaffold. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C1SP	AKOSi010-A	Induced pluripotent stem cell	Female
CVCL_C9HV	AKOSi011-A	Induced pluripotent stem cell	Female
CVCL_C9HW	AKOSi012-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00346853	PHASE1	COMPLETED	Phase 1 Pilot Study of 4-MP to Treat Stargardt Macular Dystrophy
NCT07267026	PHASE1	RECRUITING	A Study to Evaluate the Safety, Tolerability and PK of SK-09
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia