ACSF3

Summary

ACSF3 (acyl-CoA synthetase family member 3, HGNC:27288) is a protein-coding gene on chromosome 16q24.3, encoding Malonate–CoA ligase ACSF3, mitochondrial (Q4G176). Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.

This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 197322 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined malonic and methylmalonic acidemia (Definitive, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 1,189 total — 78 pathogenic, 100 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001243279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27288
Approved symbol	ACSF3
Name	acyl-CoA synthetase family member 3
Location	16q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000176715
Ensembl biotype	protein_coding
OMIM	614245
Entrez	197322

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000317447, ENST00000378345, ENST00000393145, ENST00000406948, ENST00000535176, ENST00000537116, ENST00000537155, ENST00000537290, ENST00000537895, ENST00000538340, ENST00000540697, ENST00000541755, ENST00000542688, ENST00000543676, ENST00000544543, ENST00000562204, ENST00000562750, ENST00000614302, ENST00000649953, ENST00000871966, ENST00000871967, ENST00000871968, ENST00000966008

RefSeq mRNA: 4 — MANE Select: NM_001243279 NM_001127214, NM_001243279, NM_001284316, NM_174917

CCDS: CCDS10974, CCDS73926

Canonical transcript exons

ENST00000614302 — 11 exons

Exon	Start	End
ENSE00001257027	89114339	89114487
ENSE00001257031	89112092	89112246
ENSE00001311992	89100662	89101347
ENSE00001322646	89098591	89098763
ENSE00003471806	89145938	89146049
ENSE00003605484	89145267	89145401
ENSE00003636915	89120801	89120913
ENSE00003671887	89102604	89102759
ENSE00003728070	89093852	89093996
ENSE00003751317	89154090	89156233
ENSE00003784924	89133136	89133262

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 93.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8936 / max 124.8042, expressed in 1789 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155568	8.2311	1783
155567	1.3891	888
155571	0.1279	37
155570	0.0504	17
155572	0.0262	9
155569	0.0230	8
155573	0.0213	6
155574	0.0135	4
208007	0.0111	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	93.51	gold quality
granulocyte	CL:0000094	92.37	gold quality
right adrenal gland	UBERON:0001233	91.57	gold quality
sural nerve	UBERON:0015488	91.52	gold quality
bone marrow cell	CL:0002092	91.23	gold quality
right adrenal gland cortex	UBERON:0035827	91.20	gold quality
left adrenal gland	UBERON:0001234	90.25	gold quality
left adrenal gland cortex	UBERON:0035825	89.96	gold quality
right lobe of liver	UBERON:0001114	89.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.81	gold quality
vermiform appendix	UBERON:0001154	89.56	gold quality
colonic epithelium	UBERON:0000397	89.43	gold quality
adrenal tissue	UBERON:0018303	89.36	gold quality
transverse colon	UBERON:0001157	89.18	gold quality
adrenal gland	UBERON:0002369	89.10	gold quality
adrenal cortex	UBERON:0001235	88.39	gold quality
small intestine	UBERON:0002108	88.30	gold quality
leukocyte	CL:0000738	88.23	gold quality
monocyte	CL:0000576	88.16	gold quality
right lobe of thyroid gland	UBERON:0001119	87.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.91	gold quality
spleen	UBERON:0002106	87.61	gold quality
rectum	UBERON:0001052	87.53	gold quality
body of stomach	UBERON:0001161	87.41	gold quality
body of pancreas	UBERON:0001150	87.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.13	gold quality
lymph node	UBERON:0000029	87.00	gold quality
lower esophagus mucosa	UBERON:0035834	86.96	gold quality
right uterine tube	UBERON:0001302	86.68	gold quality
left lobe of thyroid gland	UBERON:0001120	86.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16
E-MTAB-6379	no	114.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting ACSF3, 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-4283	100.00	66.42	2097
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-5001-5P	99.05	66.76	1972

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• ACSF3 is a candidate gene for non-classical CMAMMA observed in our patients. (PMID:21785126)
• mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase, were identified as a cause of combined malonic and methylmalonic aciduria. (PMID:21841779)
• Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis. (PMID:21846720)
• data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of immunoglobulin heavy chain translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma. (PMID:22420028)
• ACSF3 was significantly upregulated, and was involved in fatty acid and lipid metabolism and accelerated liver injury in alcoholic liver disease. (PMID:23337955)
• an essential role for ACSF3 in dictating the metabolic fate of mitochondrial malonate and malonyl-CoA in mammalian metabolism (PMID:28479296)
• ACSF3-derived malonyl-CoA can be used to malonylate lysine residues on proteins within the matrix of mitochondria, possibly adding another regulatory layer to post-translational control of mitochondrial metabolism. (PMID:30201289)
• Causal ACSF3 mutations were identified in all patients. (PMID:30740739)
• ACSF3 catalyzes the first step of mitochondrial fatty acid biosynthesis (mtFASII). Hypofunctional mtFASII impairs mitochondrial flexibility and lipoylation degree. Defective mtFASII leads to reduced glycolytic flux and upregulation of beta-oxidation. (PMID:31376476)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ACSF3	ENSDARG00000059503
mus_musculus	Acsf3	ENSMUSG00000015016
rattus_norvegicus	Acsf3	ENSRNOG00000015077
drosophila_melanogaster	Acsf3	FBGN0029945
caenorhabditis_elegans		WBGENE00016849
caenorhabditis_elegans		WBGENE00018269

Paralogs (13): ACSM3 (ENSG00000005187), ACSM2B (ENSG00000066813), AACS (ENSG00000081760), ACSS3 (ENSG00000111058), ACSS2 (ENSG00000131069), ACSS1 (ENSG00000154930), AASDH (ENSG00000157426), ACSM1 (ENSG00000166743), ACSF2 (ENSG00000167107), ACSM6 (ENSG00000173124), ACSM5 (ENSG00000183549), ACSM2A (ENSG00000183747), ACSM4 (ENSG00000215009)

Protein

Protein identifiers

Malonate–CoA ligase ACSF3, mitochondrial — Q4G176 (reviewed: Q4G176)

Alternative names: Acyl-CoA synthetase family member 3

All UniProt accessions (12): Q4G176, A0A3B3ISK9, F5GX20, F5H2G6, F5H362, F5H3B2, F5H5A1, F5H755, H0YGC7, H0YGJ0, H0YH37, H3BTS0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester. May have some preference toward very-long-chain substrates.

Subcellular location. Mitochondrion.

Disease relevance. Combined malonic and methylmalonic aciduria (CMAMMA) [MIM:614265] A metabolic disease characterized by malonic and methylmalonic aciduria, with urinary excretion of much larger amounts of methylmalonic acid than malonic acid, in the presence of normal malonyl-CoA decarboxylase activity. Clinical features include coma, ketoacidosis, hypoglycemia, failure to thrive, microcephaly, dystonia, axial hypotonia and/or developmental delay, and neurologic manifestations including seizures, psychiatric disease and/or cognitive decline. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ATP-dependent AMP-binding enzyme family.

RefSeq proteins (4): NP_001120686, NP_001230208, NP_001271245, NP_777577 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000873	AMP-dep_synth/lig_dom	Domain
IPR020845	AMP-binding_CS	Conserved_site
IPR025110	AMP-bd_C	Domain
IPR042099	ANL_N_sf	Homologous_superfamily
IPR045851	AMP-b_sf	Homologous_superfamily

Pfam: PF00501, PF13193

Catalyzed reactions (Rhea), 2 shown:

• malonate + ATP + CoA = malonyl-CoA + AMP + diphosphate (RHEA:32139)
• tetracosanoate + ATP + CoA = tetracosanoyl-CoA + AMP + diphosphate (RHEA:33639)

UniProt features (23 total): sequence variant 13, binding site 4, mutagenesis site 2, sequence conflict 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4G176-F1	86.58	0.68

Functional residue map

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

Ligand- & substrate-binding residues (4): 202–210; 457; 471; 563

Mutagenesis-validated functional residues (2):

Position	Phenotype
354	impairs malonyl-coa synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-75876	Synthesis of very long-chain fatty acyl-CoAs
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-75105	Fatty acyl-CoA biosynthesis
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 168 (showing top): REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS

GO Biological Process (5): fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), malonate catabolic process (GO:0090410), lipid metabolic process (GO:0006629)

GO Molecular Function (7): ATP binding (GO:0005524), CoA-ligase activity (GO:0016405), very long-chain fatty acid-CoA ligase activity (GO:0031957), malonyl-CoA synthetase activity (GO:0090409), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Fatty acyl-CoA biosynthesis	1
Metabolism	1
Fatty acid metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	1
monocarboxylic acid metabolic process	1
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
long-chain fatty-acyl-CoA metabolic process	1
fatty-acyl-CoA biosynthetic process	1
dicarboxylic acid catabolic process	1
primary metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
acid-thiol ligase activity	1
fatty acid-CoA ligase activity	1
CoA-ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2697 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACSF3	MMAB	Q96EY8	624
ACSF3	MMADHC	Q9H3L0	595
ACSF3	DHRS12	A0PJE2	573
ACSF3	MLYCD	O95822	526
ACSF3	MCEE	Q96PE7	488
ACSF3	FASN	P49327	458
ACSF3	AACS	Q86V21	439
ACSF3	ITPK1	Q13572	420
ACSF3	LMBRD1	Q9NUN5	419
ACSF3	HIBCH	Q6NVY1	398
ACSF3	OR1L1	Q8NH94	390
ACSF3	SLC22A31	A6NKX4	390
ACSF3	AASDH	Q4L235	388
ACSF3	TRAPPC2L	Q9UL33	386
ACSF3	MCAT	Q8IVS2	377

IntAct

82 interactions, top by confidence:

A	B	Type	Score
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
ACSF3	LONP1	psi-mi:“MI:0915”(physical association)	0.590
LONP1	ACSF3	psi-mi:“MI:0915”(physical association)	0.590
KCTD14	ACSF3	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	ACSF3	psi-mi:“MI:0915”(physical association)	0.560
ACSF3	KRT40	psi-mi:“MI:0915”(physical association)	0.560
ACSF3	PPP1R13B	psi-mi:“MI:0915”(physical association)	0.560
MATN4	ACSF3	psi-mi:“MI:0915”(physical association)	0.560
RAB28	ACSF3	psi-mi:“MI:0915”(physical association)	0.560
KCTD14	ACSF3	psi-mi:“MI:0914”(association)	0.560
GLP1R	ACSF3	psi-mi:“MI:0915”(physical association)	0.540
ACSF3	GLP1R	psi-mi:“MI:0403”(colocalization)	0.540
ACSF3	GLP1R	psi-mi:“MI:0915”(physical association)	0.540
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
SDHB	POLG	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
TRMT61B	GLS	psi-mi:“MI:0914”(association)	0.480
ACSF3	ABHD10	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
HAUS2	SCAMP3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (75): ACSF3 (Affinity Capture-RNA), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS), ACSF3 (Affinity Capture-RNA), ACSF3 (Affinity Capture-MS)

ESM2 similar proteins: A6QP05, A9JS71, F1NB38, F1R6N4, O35459, P11172, P13439, P17256, P23965, P31754, P42125, P42126, Q03426, Q0V8R7, Q13011, Q28C91, Q28DB5, Q2HJD5, Q3MIE0, Q3URE1, Q4G176, Q58DN7, Q5E9H9, Q5E9T8, Q5HZQ8, Q5R4W0, Q5R514, Q5R824, Q5REX5, Q5RFG0, Q62651, Q62904, Q64323, Q6AYG5, Q6GLK6, Q6GM82, Q6NYL5, Q6PE15, Q7T0X7, Q8BGT5

Diamond homologs: A0A0C1BUW8, A0A0C1E3B7, A0A0S1RUN4, A0A0S2E7V8, A0A0S2E7W3, A0A0S2E7W7, A0A0S2E7X0, A0A0S2E7Z1, A0A336U965, A0A384XH94, A0A3G1DJF8, A0A455LXK0, A0A455M7S4, A0A5K6CNB8, A0A6F9DYX9, A4YDR9, A7XRY0, A7Z809, B6HJU6, B7STY1, B8MV60, B8MYS6, C1CB20, C1CNE9, C5D6U5, C5NN18, C8VTR6, E1ACQ0, F8P1W3, I1RF58, I6NXV7, I6X8D2, L7WU80, O22898, O53521, P0A398, P0A399, P0DX14, P38137, P44446

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1189 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	78
Likely pathogenic	100
Uncertain significance	318
Likely benign	500
Benign	80

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072093	NC_000016.9:g.(?89199534)(89199680_?)del	Pathogenic
1072094	NC_000016.9:g.(?89160207)(89212467_?)del	Pathogenic
1072095	NC_000016.9:g.(?89167070)(89180915_?)del	Pathogenic
1072096	NC_000016.9:g.(?89178490)(89207694_?)del	Pathogenic
1072097	NC_000016.9:g.(?89187199)(89222264_?)del	Pathogenic
1072354	NM_001243279.3(ACSF3):c.186_196dup (p.His66fs)	Pathogenic
1074075	NC_000016.10:g.89112092del	Pathogenic
1074796	NC_000016.9:g.(?88709737)(89220635_?)del	Pathogenic
1341552	NC_000016.9:g.88365786_89584412del1218627	Pathogenic
1396014	NM_001243279.3(ACSF3):c.1643C>A (p.Ser548Ter)	Pathogenic
1441215	NC_000016.9:g.(?89164989)(89222264_?)del	Pathogenic
1452052	NC_000016.9:g.(?89160207)(89203247_?)del	Pathogenic
1457547	NM_001243279.3(ACSF3):c.1104del (p.Thr369fs)	Pathogenic
1459439	NM_001243279.3(ACSF3):c.1613+2T>C	Pathogenic
1460177	NC_000016.9:g.(?89183388)(89187331_?)del	Pathogenic
150450	GRCh38/hg38 16q23.1-24.3(chr16:75377981-90081992)x3	Pathogenic
150862	GRCh38/hg38 16q24.1-24.3(chr16:85552976-90096995)x3	Pathogenic
152591	GRCh38/hg38 16q23.2-24.3(chr16:80717291-90096662)x3	Pathogenic
154631	GRCh38/hg38 16q23.2-24.3(chr16:80067315-90057871)x3	Pathogenic
155557	GRCh38/hg38 16q24.1-24.3(chr16:86950106-89335814)x1	Pathogenic
1807841	GRCh37/hg19 16q24.3(chr16:89134318-89434509)x1	Pathogenic
1978114	NM_001243279.3(ACSF3):c.1029G>A (p.Trp343Ter)	Pathogenic
1994991	NM_001243279.3(ACSF3):c.1632C>A (p.Tyr544Ter)	Pathogenic
2004584	NM_001243279.3(ACSF3):c.295_296del (p.Ser99fs)	Pathogenic
2005549	NM_001243279.3(ACSF3):c.1137dup (p.Thr380fs)	Pathogenic
2027064	NM_001243279.3(ACSF3):c.1183del (p.Gln395fs)	Pathogenic
2028960	NM_001243279.3(ACSF3):c.1219G>T (p.Gly407Ter)	Pathogenic
2107530	NM_001243279.3(ACSF3):c.448C>T (p.Gln150Ter)	Pathogenic
2116733	NM_001243279.3(ACSF3):c.1183C>T (p.Gln395Ter)	Pathogenic
2125525	NM_001243279.3(ACSF3):c.928C>T (p.Gln310Ter)	Pathogenic

SpliceAI

3313 predictions. Top by Δscore:

Variant	Effect	Δscore
16:89093946:G:GT	donor_gain	1.0000
16:89093993:G:GG	donor_gain	1.0000
16:89102756:GCAG:G	donor_gain	1.0000
16:89102757:CAGGT:C	donor_loss	1.0000
16:89102758:AGGTG:A	donor_loss	1.0000
16:89102760:GT:G	donor_loss	1.0000
16:89102761:T:G	donor_loss	1.0000
16:89112244:TAGG:T	donor_loss	1.0000
16:89112245:AGGT:A	donor_loss	1.0000
16:89112246:GGT:G	donor_loss	1.0000
16:89112248:T:A	donor_loss	1.0000
16:89133131:CACA:C	acceptor_loss	1.0000
16:89133134:A:AG	acceptor_gain	1.0000
16:89133134:AG:A	acceptor_gain	1.0000
16:89133135:G:GA	acceptor_gain	1.0000
16:89133135:GG:G	acceptor_gain	1.0000
16:89133135:GGT:G	acceptor_gain	1.0000
16:89133135:GGTGA:G	acceptor_gain	1.0000
16:89133258:GACAG:G	donor_gain	1.0000
16:89145264:CAGGG:C	acceptor_loss	1.0000
16:89145265:A:AG	acceptor_gain	1.0000
16:89145265:AG:A	acceptor_gain	1.0000
16:89145265:AGG:A	acceptor_gain	1.0000
16:89145266:G:GG	acceptor_gain	1.0000
16:89145266:GG:G	acceptor_gain	1.0000
16:89145266:GGG:G	acceptor_gain	1.0000
16:89145400:AGG:A	donor_loss	1.0000
16:89145402:GT:G	donor_loss	1.0000
16:89145403:T:G	donor_loss	1.0000
16:89146029:G:GT	donor_gain	1.0000

AlphaMissense

3705 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:89145989:C:A	A518D	0.992
16:89145378:T:C	L493P	0.991
16:89114437:A:T	E359V	0.990
16:89101108:A:C	S143R	0.989
16:89101110:C:A	S143R	0.989
16:89101110:C:G	S143R	0.989
16:89114388:T:A	W343R	0.989
16:89114388:T:C	W343R	0.989
16:89154174:G:C	K566N	0.989
16:89154174:G:T	K566N	0.989
16:89101288:A:C	S203R	0.988
16:89101290:T:A	S203R	0.988
16:89101290:T:G	S203R	0.988
16:89114434:C:T	T358I	0.988
16:89101018:T:A	W113R	0.987
16:89101018:T:C	W113R	0.987
16:89145312:G:C	R471P	0.987
16:89145943:G:C	A503P	0.987
16:89100904:A:C	S75R	0.986
16:89100906:C:A	S75R	0.986
16:89100906:C:G	S75R	0.986
16:89145947:T:A	V504E	0.986
16:89133193:T:C	F433L	0.985
16:89133195:T:A	F433L	0.985
16:89133195:T:G	F433L	0.985
16:89154116:C:A	P547H	0.984
16:89101049:T:A	V123D	0.983
16:89133253:T:C	F453L	0.983
16:89133255:T:A	F453L	0.983
16:89133255:T:G	F453L	0.983

dbSNP variants (sampled 300 via entrez): RS1000013349 (16:89154124 C>G,T), RS1000074593 (16:89149344 T>C), RS1000092399 (16:89121246 C>G,T), RS1000147755 (16:89149137 G>A,C), RS1000197422 (16:89129908 T>G), RS1000263358 (16:89105564 G>A), RS1000347357 (16:89102253 G>A,T), RS1000354399 (16:89105839 G>A,C), RS1000399921 (16:89102381 C>T), RS1000489706 (16:89138110 G>A), RS1000531300 (16:89117736 C>A,T), RS1000566397 (16:89137794 C>A), RS1000597612 (16:89106583 T>C), RS1000624300 (16:89114722 C>A,T), RS1000718766 (16:89142321 C>A)

Disease associations

OMIM: gene MIM:614245 | disease phenotypes: MIM:614265, MIM:233690, MIM:148050, MIM:251000, MIM:616726, MIM:227650, MIM:614541

GenCC curated gene-disease

Disease	Classification	Inheritance
combined malonic and methylmalonic acidemia	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
combined malonic and methylmalonic acidemia	Definitive	AR

Mondo (7): combined malonic and methylmalonic acidemia (MONDO:0013661), granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (MONDO:0009308), KBG syndrome (MONDO:0007846), methylmalonic acidemia (MONDO:0002012), primary ciliary dyskinesia 33 (MONDO:0014750), Fanconi anemia (MONDO:0019391), chromosome 16q22 deletion syndrome (MONDO:0013798)

Orphanet (7): Combined malonic and methylmalonic acidemia (Orphanet:289504), Chronic granulomatous disease (Orphanet:379), KBG syndrome (Orphanet:2332), Syndromic anorectal malformation (Orphanet:117573), Primary ciliary dyskinesia (Orphanet:244), Fanconi anemia (Orphanet:84), 16q22 deletion syndrome (Orphanet:658540)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000708	Atypical behavior
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001941	Acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001993	Ketoacidosis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002076	Migraine
HP:0002254	Intermittent diarrhea
HP:0002354	Memory impairment
HP:0002384	Focal impaired awareness seizure
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002912	Methylmalonic acidemia
HP:0003215	Dicarboxylic aciduria
HP:0008936	Axial hypotonia
HP:0011169	Generalized clonic seizure
HP:0012120	Methylmalonic aciduria
HP:0031064	Impaired continence
HP:0040145	Dicarboxylic acidemia
HP:0040288	Nasogastric tube feeding

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST008058_183	Estimated glomerular filtration rate	6.000000e-07
GCST008059_223	Estimated glomerular filtration rate	3.000000e-07
GCST012081_5	Response to tofacitinib treatment (herpes zoster)	3.000000e-08
GCST012082_5	Response to tofacitinib treatment (herpes zoster)(time to event)	2.000000e-08
GCST012084_4	Response to tofacitinib treatment in rheumatoid arthritis (herpes zoster)	2.000000e-06
GCST012086_4	Response to tofacitinib treatment in rheumatoid arthritis (herpes zoster)(time to event)	7.000000e-07

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
C580002	Combined Malonic and Methylmalonic Aciduria (supp.)
C565533	Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome B-Negative (supp.)
C537015	KBG syndrome (supp.)
C537358	Methylmalonic acidemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523315 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	4
Cadmium Chloride	decreases expression	2
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases expression, increases abundance	1
Doxorubicin	decreases expression	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4415382	Binding	Binding affinity to ACSF3 in human PC9 cells incubated for 1 hr by ABPP-SILAC assay	Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3Z0	WG2731	Finite cell line	Male
CVCL_B3Z3	WG2837	Finite cell line	Male
CVCL_D8DQ	Ubigene AGS ACSF3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06465641	PHASE4	RECRUITING	Methylphenidate in KBG Syndrome: N-of-1 Series
NCT02426775	PHASE3	COMPLETED	Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia
NCT07163364	PHASE3	NOT_YET_RECRUITING	A Study to Evaluate the Effects and Safety of Hydroxocobalamin in Participants With Combined Methylmalonic Academia (cblC Type)
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT01341379	PHASE2	WITHDRAWN	Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate
NCT01597440	PHASE2	TERMINATED	Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
NCT01599286	PHASE2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT04732429	PHASE2	TERMINATED	Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00001749	PHASE2	COMPLETED	Medical Treatment for Diamond Blackfan Anemia
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT00053989	PHASE2	COMPLETED	NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders
NCT00084695	PHASE2	UNKNOWN	Umbilical Cord Blood for Stem Cell Transplantation in Treating Young Patients With Malignant or Nonmalignant Diseases
NCT00258427	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia
NCT00453388	PHASE2	COMPLETED	Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia
NCT01071239	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplant for Fanconi Anemia
NCT02143830	PHASE2	RECRUITING	HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy
NCT02931071	PHASE2	COMPLETED	Clinical Phase II Trial to Evaluate CD34+ Cells Mobilization and Collection in Patients With Fanconi Anemia for Subsequent Transduction With a Lentiviral Vector Carring FANCA Gene. FANCOSTEM-1
NCT03206086	PHASE2	ACTIVE_NOT_RECRUITING	Eltrombopag for People With Fanconi Anemia
NCT03398824	PHASE2	COMPLETED	Pilot Study of Metformin for Patients With Fanconi Anemia
NCT03476330	PHASE2	COMPLETED	Quercetin Chemoprevention for Squamous Cell Carcinoma in Patients With Fanconi Anemia
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT03600909	PHASE2	TERMINATED	A Study of the Effect of Blood Stem Cell Transplant After Chemotherapy Alone in Patients With Fanconi Anemia
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT06045052	PHASE2	COMPLETED	Eltrombopag for Treatment of Fanconi Anemia
NCT04836494	PHASE1	TERMINATED	A First in Human, Dose Escalation Study to Evaluate the Safety and Tolerability of BBP-671 in Healthy Volunteers and Patients With Propionic Acidemia or Methylmalonic Acidemia
NCT00001399	PHASE1	COMPLETED	Gene Therapy for the Treatment of Fanconi’s Anemia Type C
NCT00005896	PHASE1	UNKNOWN	Phase I Pilot Study of CD34 Enriched, Fanconi’s Anemia Complementation Group C Gene Transduced Autologous Peripheral Blood Stem Cell Transplantation in Patients With Fanconi’s Anemia
NCT00006127	PHASE1	UNKNOWN	Phase I Study of Amifostine in Patients With Bone Marrow Failure Related to Fanconi’s Anemia
NCT00093743	PHASE1	COMPLETED	Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia
NCT00243399	PHASE1	COMPLETED	Oxandrolone for the Treatment of Bone Marrow Aplasia in Fanconi Anemia
NCT00272857	PHASE1	COMPLETED	Bone Marrow Cell Gene Transfer in Individuals With Fanconi Anemia
NCT00317876	PHASE1	COMPLETED	Cyclophosphamide in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Fanconi’s Anemia
NCT00586274	PHASE1	TERMINATED	Use of Rft5-Dga to Deplete Alloreactive Cells for Pts With Fanconi Anemia After Haploidentical SCT
NCT01331018	PHASE1	TERMINATED	Gene Therapy for Fanconi Anemia
NCT01720147	PHASE1	COMPLETED	Quercetin in Children With Fanconi Anemia; a Pilot Study
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT03810690	PHASE1/PHASE2	WITHDRAWN	Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia