FASTKD2

Summary

FASTKD2 (FAST kinase domains 2, HGNC:29160) is a protein-coding gene on chromosome 2q33.3, encoding FAST kinase domain-containing protein 2, mitochondrial (Q9NYY8). Plays an important role in assembly of the mitochondrial large ribosomal subunit.

This gene encodes a protein that is localized in the mitochondrial inner compartment and that may play a role in mitochondrial apoptosis. Nonsense mutations have been reported to result in cytochrome c oxidase deficiency.

Source: NCBI Gene 22868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 528 total — 14 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 51
• MANE Select transcript: NM_001136193

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29160
Approved symbol	FASTKD2
Name	FAST kinase domains 2
Location	2q33.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000118246
Ensembl biotype	protein_coding
OMIM	612322
Entrez	22868

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 retained_intron

ENST00000236980, ENST00000402774, ENST00000403094, ENST00000418289, ENST00000471788, ENST00000487777, ENST00000870593, ENST00000870594, ENST00000870595, ENST00000870596, ENST00000918135, ENST00000918136, ENST00000966849, ENST00000966850, ENST00000966851, ENST00000966852

RefSeq mRNA: 3 — MANE Select: NM_001136193 NM_001136193, NM_001136194, NM_014929

CCDS: CCDS2371

Canonical transcript exons

ENST00000402774 — 12 exons

Exon	Start	End
ENSE00001351723	206790572	206790686
ENSE00001549431	206765606	206765747
ENSE00001945803	206791683	206796189
ENSE00003492550	206771894	206772017
ENSE00003500304	206771182	206771290
ENSE00003582954	206787937	206788155
ENSE00003585634	206774225	206774397
ENSE00003615253	206788819	206788903
ENSE00003620400	206766644	206767470
ENSE00003633559	206772181	206772320
ENSE00003662204	206770091	206770194
ENSE00003675660	206786733	206786899

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 92.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.3034 / max 406.6553, expressed in 1791 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24839	28.0732	1790
24840	1.2302	791

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	92.30	gold quality
secondary oocyte	CL:0000655	91.26	gold quality
gastrocnemius	UBERON:0001388	90.83	gold quality
oocyte	CL:0000023	90.55	gold quality
muscle of leg	UBERON:0001383	90.39	gold quality
biceps brachii	UBERON:0001507	89.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.46	gold quality
calcaneal tendon	UBERON:0003701	89.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.82	gold quality
heart left ventricle	UBERON:0002084	88.80	gold quality
heart right ventricle	UBERON:0002080	88.69	gold quality
cardiac ventricle	UBERON:0002082	88.63	gold quality
islet of Langerhans	UBERON:0000006	88.57	gold quality
muscle organ	UBERON:0001630	88.52	gold quality
skeletal muscle organ	UBERON:0014892	88.52	gold quality
rectum	UBERON:0001052	88.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.96	gold quality
heart	UBERON:0000948	87.43	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.23	gold quality
right atrium auricular region	UBERON:0006631	86.94	gold quality
right adrenal gland	UBERON:0001233	86.72	gold quality
right adrenal gland cortex	UBERON:0035827	86.46	gold quality
left adrenal gland	UBERON:0001234	86.41	gold quality
adrenal gland	UBERON:0002369	86.28	gold quality
skeletal muscle tissue	UBERON:0001134	86.22	gold quality
esophagus mucosa	UBERON:0002469	86.18	gold quality
left adrenal gland cortex	UBERON:0035825	86.08	gold quality
apex of heart	UBERON:0002098	86.07	gold quality
cardiac atrium	UBERON:0002081	86.04	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DHX30

miRNA regulators (miRDB)

89 targeting FASTKD2, 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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-149-3P	99.72	68.22	3963

Literature-anchored findings (GeneRIF, showing 9)

• mutation in a gene segregating with a peculiar mitochondrial encephalomyopathy associated with COX deficiency in skeletal muscle. FASTKD2 is localized in the mitochondrial inner compartment. (PMID:18771761)
• regulation of FASTKD2 by NRIF3 and the DIF-1 complex acts as a novel death switch that selectively modulates apoptosis in breast cancer (PMID:21444724)
• Authors discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2) with better memory performance (PMID:25385369)
• Fas Activated Serine-Threonine Kinase Domains 2 (FASTKD2) mediates apoptosis of breast and prostate cancer cells through its novel FAST2 domain. (PMID:25409762)
• CRISPR-mediated deletion of FASTKD2 leads to aberrant processing. (PMID:26370583)
• Despite the fact that proteins of the FASTK family FASTKD1-5 share the same domains, they exhibit various-sometimes opposing-functions in almost all steps of mitochondrial RNA metabolism. (PMID:29036396)
• FASTKD2 promotes cancer cell progression through upregulating Myc expression in pancreatic ductal adenocarcinoma. (PMID:31692063)
• Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency. (PMID:31944455)
• A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome. (PMID:35729327)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fastkd2	ENSDARG00000074031
mus_musculus	Fastkd2	ENSMUSG00000025962
rattus_norvegicus	Fastkd2	ENSRNOG00000023923

Paralogs (5): FASTKD3 (ENSG00000124279), TBRG4 (ENSG00000136270), FASTKD1 (ENSG00000138399), FASTK (ENSG00000164896), FASTKD5 (ENSG00000215251)

Protein

Protein identifiers

FAST kinase domain-containing protein 2, mitochondrial — Q9NYY8 (reviewed: Q9NYY8)

All UniProt accessions (2): Q9NYY8, C9JPI6

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in assembly of the mitochondrial large ribosomal subunit. As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mitochondrial ribosomal RNA (16S mt-rRNA), controls 16S mt-rRNA abundance and is required for intra-mitochondrial translation. May play a role in mitochondrial apoptosis.

Subunit / interactions. Monomer. Found in a complex with GRSF1, DDX28, DHX30 and FASTKD5. Associates with the 16S mitochondrial rRNA (16S mt-rRNA). Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA.

Subcellular location. Mitochondrion matrix. Mitochondrion nucleoid.

Tissue specificity. Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in heart, smooth muscle and thyroid.

Disease relevance. Combined oxidative phosphorylation deficiency 44 (COXPD44) [MIM:618855] An autosomal recessive mitochondrial disorder characterized by onset in infancy or early childhood of global developmental delay, hypotonia, and abnormal movements. Combined oxidative phosphorylation deficiency is present in skeletal muscle. Most patients have seizures associated with status epilepticus. Additional variable features include optic atrophy, hypertrophic cardiomyopathy, stroke-like episodes, and increased lactate levels in serum and cerebrospinal fluid. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the FAST kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYY8-1	1	yes
Q9NYY8-2	2

RefSeq proteins (3): NP_001129665, NP_001129666, NP_055744 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010622	FAST_Leu-rich	Domain
IPR013579	FAST_2	Domain
IPR013584	RAP	Domain
IPR050870	FAST_kinase	Family

Pfam: PF06743, PF08368, PF08373

UniProt features (14 total): sequence variant 6, modified residue 3, splice variant 2, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYY8-F1	75.39	0.58

Functional residue map

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

Post-translational modifications (3): 126, 140, 708

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6793080	rRNA modification in the mitochondrion
R-HSA-9837092	FASTK family proteins regulate processing and stability of mitochondrial RNAs
R-HSA-9937008	Mitochondrial mRNA modification

MSigDB gene sets: 186 (showing top): GOBP_RIBOSOME_BIOGENESIS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_RIBOSOME_ASSEMBLY, TAKADA_GASTRIC_CANCER_COPY_NUMBER_DN, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, GOBP_RIBOSOMAL_LARGE_SUBUNIT_ASSEMBLY

GO Biological Process (8): mitochondrial RNA processing (GO:0000963), RNA processing (GO:0006396), apoptotic process (GO:0006915), mitochondrial translation (GO:0032543), regulation of mitochondrial mRNA stability (GO:0044528), mitochondrial large ribosomal subunit assembly (GO:1902775), ribosome biogenesis (GO:0042254), positive regulation of mitochondrial translation (GO:0070131)

GO Molecular Function (3): RNA binding (GO:0003723), rRNA binding (GO:0019843), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), ribonucleoprotein granule (GO:0035770), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
rRNA processing in the mitochondrion	1
Mitochondrial RNA degradation	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	4
mitochondrial gene expression	2
intracellular membraneless organelle	2
mitochondrial RNA metabolic process	1
RNA processing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
translation	1
regulation of mRNA stability	1
ribosomal large subunit assembly	1
mitochondrial ribosome assembly	1
ribonucleoprotein complex biogenesis	1
mitochondrial translation	1
positive regulation of translation	1
regulation of mitochondrial translation	1
nucleic acid binding	1
RNA binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
supramolecular complex	1
mitochondrial matrix	1
nucleoid	1

Protein interactions and networks

STRING

1296 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FASTKD2	FASTK	Q14296	945
FASTKD2	NGRN	Q9NPE2	861
FASTKD2	RPUSD3	Q6P087	830
FASTKD2	RPUSD4	Q96CM3	811
FASTKD2	COX6B1	P14854	793
FASTKD2	GRSF1	Q12849	763
FASTKD2	TACO1	Q9BSH4	756
FASTKD2	SCO1	O75880	740
FASTKD2	FASTKD5	Q7L8L6	736
FASTKD2	PTCD1	O75127	729
FASTKD2	LRPPRC	P42704	723
FASTKD2	RCC1L	Q96I51	698
FASTKD2	MTERF3	Q96E29	696
FASTKD2	DHX30	Q7L2E3	682
FASTKD2	COX10	Q12887	678

IntAct

133 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
FAM120A	SYNCRIP	psi-mi:“MI:0914”(association)	0.640
FASTKD2	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
FASTKD2	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEA1	MAGEB3	psi-mi:“MI:0914”(association)	0.530
HNRNPA1	PTCD1	psi-mi:“MI:0914”(association)	0.530
IGF2BP3	PTCD1	psi-mi:“MI:0914”(association)	0.530
DDX28	PTCD1	psi-mi:“MI:0914”(association)	0.530
APIP	VSIG8	psi-mi:“MI:0914”(association)	0.530
MRPL13	GTPBP10	psi-mi:“MI:0914”(association)	0.530
DCAF8	DCAF8L1	psi-mi:“MI:0914”(association)	0.530
ILF2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RBM3	PRMT5	psi-mi:“MI:0914”(association)	0.530
CIRBP	PRMT5	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
FASTKD2	CFTR	psi-mi:“MI:0915”(physical association)	0.520
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
MRPL50	MRPL43	psi-mi:“MI:0914”(association)	0.350
USP7	STIL	psi-mi:“MI:0914”(association)	0.350

BioGRID (343): FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), CLTC (Co-fractionation), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), FASTKD2 (Affinity Capture-MS), NGRN (Affinity Capture-MS), WBSCR16 (Affinity Capture-MS)

ESM2 similar proteins: A6QPR9, E2RDV1, O00472, O75665, P40630, P55265, Q00059, Q0II87, Q13426, Q149N8, Q15650, Q2TBQ7, Q3B8D4, Q3UY96, Q3ZBU9, Q498D5, Q4H0T5, Q4KM51, Q4R7Q1, Q4R914, Q5D144, Q5HZY0, Q5M7V7, Q5R4I3, Q5R776, Q5SSK3, Q5VJS5, Q5ZKF4, Q68CZ1, Q6AZF8, Q6DIJ5, Q6ZMV9, Q6ZWJ1, Q8BSE0, Q8CG73, Q8IZC4, Q8L7K4, Q8NA72, Q8NE18, Q91ZW1

Diamond homologs: Q5M7V7, Q5R776, Q922E6, Q9NYY8, Q14CZ7, Q68FN9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DHX30	“down-regulates quantity by repression”	FASTKD2	“transcriptional regulation”
FASTKD2	up-regulates	Stress_granules

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial ribosome-associated quality control	13	18.6×	6e-11
Mitochondrial translation initiation	11	16.2×	8e-09
Mitochondrial translation elongation	11	16.2×	8e-09
Mitochondrial translation	10	16.0×	4e-08
Mitochondrial translation termination	11	14.1×	3e-08
mRNA 3’-end processing	5	11.4×	3e-03
Transport of Mature mRNA derived from an Intron-Containing Transcript	6	10.6×	1e-03
Translation	12	8.7×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of mitochondrial translation	5	43.5×	2e-05
positive regulation of mRNA splicing, via spliceosome	5	21.1×	6e-04
mitochondrial translation	13	17.5×	3e-10
regulation of alternative mRNA splicing, via spliceosome	6	11.4×	1e-03
negative regulation of translation	7	10.6×	6e-04
translation	12	9.6×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	12
Uncertain significance	295
Likely benign	118
Benign	32

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1952979	NM_001136193.2(FASTKD2):c.1552C>T (p.Gln518Ter)	Pathogenic
2004947	NM_001136193.2(FASTKD2):c.1388dup (p.Tyr463Ter)	Pathogenic
2828945	NM_001136193.2(FASTKD2):c.192del (p.His65fs)	Pathogenic
2968694	NM_001136193.2(FASTKD2):c.319_323del (p.Leu107fs)	Pathogenic
3233943	NM_001136193.2(FASTKD2):c.1644_1647del (p.Leu549fs)	Pathogenic
3585327	NM_001136193.2(FASTKD2):c.537del (p.Pro180fs)	Pathogenic
3629798	NM_001136193.2(FASTKD2):c.1036C>T (p.Gln346Ter)	Pathogenic
3901532	NM_001136193.2(FASTKD2):c.1115-1G>T	Pathogenic
4813513	NM_001136193.2(FASTKD2):c.1021del (p.Ser341fs)	Pathogenic
800306	NM_001136193.2(FASTKD2):c.1861del (p.Ser621fs)	Pathogenic
800307	NM_001136193.2(FASTKD2):c.810_820dup (p.Ser274fs)	Pathogenic
800308	NM_001136193.2(FASTKD2):c.868C>T (p.Arg290Ter)	Pathogenic
870460	NM_001136193.2(FASTKD2):c.613C>T (p.Arg205Ter)	Pathogenic
870461	NM_001136193.2(FASTKD2):c.764T>C (p.Leu255Pro)	Pathogenic
1333391	NM_001136193.2(FASTKD2):c.1538del (p.Leu513fs)	Likely pathogenic
1722430	NM_001136193.2(FASTKD2):c.991-2A>G	Likely pathogenic
214350	NM_001136193.2(FASTKD2):c.682C>T (p.Gln228Ter)	Likely pathogenic
2578024	NM_001136193.2(FASTKD2):c.496_497del (p.Leu166fs)	Likely pathogenic
3380961	NM_001136193.2(FASTKD2):c.503del (p.Asp168fs)	Likely pathogenic
3585344	NM_001136193.2(FASTKD2):c.1254+1G>C	Likely pathogenic
3585346	NM_001136193.2(FASTKD2):c.1323_1341dup (p.Pro448fs)	Likely pathogenic
3585360	NM_001136193.2(FASTKD2):c.1899-2A>G	Likely pathogenic
3767188	NM_001136193.2(FASTKD2):c.1499del (p.Asp500fs)	Likely pathogenic
419835	NM_001136193.2(FASTKD2):c.478_481del (p.Ser160fs)	Likely pathogenic
4278940	NM_001136193.2(FASTKD2):c.632C>G (p.Pro211Arg)	Likely pathogenic
801861	NM_001136193.2(FASTKD2):c.1898G>T (p.Arg633Ile)	Likely pathogenic

SpliceAI

2120 predictions. Top by Δscore:

Variant	Effect	Δscore
2:206769848:A:AG	acceptor_gain	1.0000
2:206769849:G:GG	acceptor_gain	1.0000
2:206770090:GGAAC:G	acceptor_gain	1.0000
2:206771169:T:TA	acceptor_gain	1.0000
2:206771173:T:TA	acceptor_gain	1.0000
2:206771177:A:AG	acceptor_gain	1.0000
2:206771178:ACAG:A	acceptor_loss	1.0000
2:206771180:A:AG	acceptor_gain	1.0000
2:206771180:A:AT	acceptor_loss	1.0000
2:206771181:G:GT	acceptor_gain	1.0000
2:206771181:GA:G	acceptor_gain	1.0000
2:206771181:GAA:G	acceptor_gain	1.0000
2:206771181:GAAT:G	acceptor_gain	1.0000
2:206771181:GAATA:G	acceptor_gain	1.0000
2:206771287:GGAG:G	donor_gain	1.0000
2:206771288:GAG:G	donor_gain	1.0000
2:206771288:GAGG:G	donor_gain	1.0000
2:206771291:G:T	donor_loss	1.0000
2:206771292:T:G	donor_loss	1.0000
2:206771892:A:AG	acceptor_gain	1.0000
2:206771892:A:C	acceptor_loss	1.0000
2:206771893:G:GG	acceptor_gain	1.0000
2:206771893:GAT:G	acceptor_gain	1.0000
2:206772003:G:GG	donor_gain	1.0000
2:206772016:AGGTA:A	donor_loss	1.0000
2:206772018:G:GG	donor_gain	1.0000
2:206772019:T:G	donor_loss	1.0000
2:206772166:A:AG	acceptor_gain	1.0000
2:206772171:A:AG	acceptor_gain	1.0000
2:206772178:A:AG	acceptor_gain	1.0000

AlphaMissense

4737 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:206770095:G:C	R261P	0.993
2:206767396:A:C	S235R	0.990
2:206767398:T:A	S235R	0.990
2:206767398:T:G	S235R	0.990
2:206767457:T:C	L255P	0.985
2:206790577:C:A	A635D	0.983
2:206790652:G:C	R660P	0.983
2:206790672:T:C	F667L	0.980
2:206790674:T:A	F667L	0.980
2:206790674:T:G	F667L	0.980
2:206788821:T:C	F606L	0.978
2:206788823:T:A	F606L	0.978
2:206788823:T:G	F606L	0.978
2:206767400:T:C	L236P	0.977
2:206790658:T:C	L662S	0.976
2:206767202:T:C	L170S	0.973
2:206771999:T:C	C366R	0.973
2:206772241:T:C	L392P	0.972
2:206767340:T:C	L216P	0.971
2:206771278:G:C	K326N	0.970
2:206771278:G:T	K326N	0.970
2:206767210:T:C	F173L	0.969
2:206767212:T:A	F173L	0.969
2:206767212:T:G	F173L	0.969
2:206771286:T:C	L329P	0.968
2:206767469:A:C	Q259P	0.966
2:206774261:T:C	F431L	0.966
2:206774263:T:A	F431L	0.966
2:206774263:T:G	F431L	0.966
2:206786806:G:C	A501P	0.966

dbSNP variants (sampled 300 via entrez): RS1000015261 (2:206788621 G>A,T), RS1000088310 (2:206781989 C>T), RS1000250328 (2:206795677 A>G), RS1000645856 (2:206789251 G>A,T), RS1000858711 (2:206795899 C>T), RS1000924521 (2:206787048 G>A,T), RS1001110079 (2:206769520 C>T), RS1001167456 (2:206770504 G>A), RS1001213818 (2:206764238 C>T), RS1001228328 (2:206789075 C>A,T), RS1001297735 (2:206776759 A>C), RS1001310527 (2:206796142 C>T), RS1001340854 (2:206782045 C>T), RS1001407220 (2:206776381 T>A,C), RS1001597891 (2:206765116 A>G,T)

Disease associations

OMIM: gene MIM:612322 | disease phenotypes: MIM:618855, MIM:220110, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 44	Strong	Autosomal recessive
FASTKD2-related infantile mitochondrial encephalomyopathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (4): combined oxidative phosphorylation deficiency 44 (MONDO:0030020), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), Leigh syndrome (MONDO:0009723), FASTKD2-related infantile mitochondrial encephalomyopathy (MONDO:0015632)

Orphanet (1): Leigh syndrome (Orphanet:506)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001348	Brisk reflexes
HP:0001350	Slurred speech
HP:0001410	Decreased liver function
HP:0001427	Mitochondrial inheritance
HP:0001508	Failure to thrive
HP:0001639	Hypertrophic cardiomyopathy
HP:0001903	Anemia
HP:0001994	Renal Fanconi syndrome
HP:0002059	Cerebral atrophy
HP:0002078	Truncal ataxia
HP:0002098	Respiratory distress
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000839_2	Height	5.000000e-06
GCST001890_16	QT interval (drug interaction)	2.000000e-06
GCST002695_1	Episodic memory	4.000000e-09
GCST005951_45	Body mass index	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0007916	response to tricyclic antidepressant
EFO:0004333	episodic memory
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
deoxynivalenol	increases expression	2
sodium arsenite	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression, affects cotreatment	1
trichostatin A	affects expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
ICG 001	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Benzophenoneidum	increases expression	1
Caffeine	decreases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Potassium Dichromate	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5J3	HAP1 FASTKD2 (-) 2	Cancer cell line	Male
CVCL_B5J4	HAP1 FASTKD2 (-) 3	Cancer cell line	Male
CVCL_B5J5	HAP1 FASTKD2 (-) 4	Cancer cell line	Male
CVCL_XN68	HAP1 FASTKD2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells