SURF1

Summary

SURF1 (SURF1 cytochrome c oxidase assembly factor, HGNC:11474) is a protein-coding gene on chromosome 9q34.2, encoding Surfeit locus protein 1 (Q15526). Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.

This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency.

Source: NCBI Gene 6834 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 777 total — 98 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 57
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_003172

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11474
Approved symbol	SURF1
Name	SURF1 cytochrome c oxidase assembly factor
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Aliases	SHY1
Ensembl gene	ENSG00000148290
Ensembl biotype	protein_coding
OMIM	185620
Entrez	6834

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000371974, ENST00000437995, ENST00000463965, ENST00000495952, ENST00000615505, ENST00000886674, ENST00000886675, ENST00000886676

RefSeq mRNA: 2 — MANE Select: NM_003172 NM_001280787, NM_003172

CCDS: CCDS6966, CCDS75928

Canonical transcript exons

ENST00000371974 — 9 exons

Exon	Start	End
ENSE00001456594	133351758	133351982
ENSE00001456605	133356400	133356487
ENSE00003459148	133352446	133352608
ENSE00003501115	133353749	133353940
ENSE00003508017	133356269	133356320
ENSE00003534628	133354659	133354741
ENSE00003564429	133352694	133352766
ENSE00003597292	133352061	133352142
ENSE00003654394	133354824	133354957

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 96.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.6615 / max 61.4162, expressed in 1801 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102984	11.6615	1801

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	96.68	gold quality
body of pancreas	UBERON:0001150	96.67	gold quality
right lobe of liver	UBERON:0001114	96.06	gold quality
body of stomach	UBERON:0001161	96.00	gold quality
mucosa of transverse colon	UBERON:0004991	95.62	gold quality
granulocyte	CL:0000094	95.37	gold quality
right adrenal gland	UBERON:0001233	95.32	gold quality
right adrenal gland cortex	UBERON:0035827	95.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.97	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.96	gold quality
left adrenal gland cortex	UBERON:0035825	94.94	gold quality
left adrenal gland	UBERON:0001234	94.93	gold quality
lower esophagus	UBERON:0013473	94.93	gold quality
right lobe of thyroid gland	UBERON:0001119	94.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.90	gold quality
popliteal artery	UBERON:0002250	94.60	gold quality
tibial artery	UBERON:0007610	94.60	gold quality
adenohypophysis	UBERON:0002196	94.59	gold quality
right coronary artery	UBERON:0001625	94.58	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.53	gold quality
left coronary artery	UBERON:0001626	94.42	gold quality
anterior cingulate cortex	UBERON:0009835	94.39	gold quality
rectum	UBERON:0001052	94.37	gold quality
transverse colon	UBERON:0001157	94.33	gold quality
descending thoracic aorta	UBERON:0002345	94.33	gold quality
left lobe of thyroid gland	UBERON:0001120	94.29	gold quality
thoracic aorta	UBERON:0001515	94.25	gold quality
gastrocnemius	UBERON:0001388	94.24	gold quality
aorta	UBERON:0000947	94.21	gold quality
cingulate cortex	UBERON:0003027	94.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-4850	no	147.92
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, MYC, YY1

miRNA regulators (miRDB)

11 targeting SURF1, 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-548AN	99.97	70.91	2817
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-5586-5P	96.29	68.02	685

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 27)

• Three novel mutations of the SURF-1 gene were identified in Japanese patients with cytochrome c oxidase deficiency; loss of function of the SURF-1 protein; cytochrome c oxidase activity was decreased to less than 20% of the control mean. (PMID:11955926)
• new missense mutation of 574C>T in the SURF1 gene in Leigh’s syndrome (PMID:12515039)
• Two novel pathogenic SURF1 mutations have been identified in a patient with Leigh syndrome. (PMID:12538779)
• Mutations in the nuclear SURF1 gene are specifically associated with cytochrome c oxidase (COX)-deficient Leigh syndrome. MR imaging abnormalities in three children with this condition involved the brain. (PMID:12812953)
• Four pathogenic mutations including a novel, in-frame, 15-bp tandem duplication (806-820) in exon 8 and a novel 751+1G>A splice site mutation in SURF1 in three cases of Leigh Syndrome with cytochrome c oxidase deficiency (PMID:14557577)
• study points to a role for surfeit 1(SURF1) in promoting the association of cytochrome c oxidase II with the cytochrome c oxidase I.cytochrome c oxidase subunit 4.cytochrome c oxidase subunit 5A subassembly (PMID:14607829)
• a SURF1 mutation may have a role in subacute encephalopathy (PMID:15214016)
• Surf1p plays a role in facilitating the insertion of heme a3 into the active site of cytochrome-c oxidase. (PMID:15764605)
• The consequences of SCO2 and SURF1 mutations suggest the existence of tissue-specific functional differences of these proteins that may serve different tissue-specific requirements for the regulation of COX biogenesis. (PMID:16083427)
• Histological and histochemical features of muscle of genetically homogenous SURF1-deficient LS were reproducible in detection of COX deficit. SURF1-deficient muscle assessed in the microscopy panel may be interpreted as normal if COX staining is not used. (PMID:17908801)
• Data show high prevalence of SURF1 c.845_846delCT mutation in Polish Leigh patients. (PMID:18583168)
• SURF1-deficient samples analyzed showed a tissue-specific copper deficiency similar to that of SCO-deficient samples, suggesting a role for Surf1 in copper homeostasis regulation (PMID:19295170)
• a direct role of Surf1 in heme a cofactor insertion into COX subunit I by providing a protein-bound heme a pool. (PMID:19625251)
• The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients. (PMID:19780766)
• mutations (574-575insCTGT, 311-321del10insAT and IVS8-1G>) were also frequent in the Russian population. (PMID:20436434)
• Analysis of mutations in the SURF1 homolog Shy1 revealed Coa4, a new member of the cytochrome oxidase assembly factor family. (PMID:20624914)
• sequenced the SURF1 gene and identified two heterozygous mutations; c.49+1 G>T and c.752_753del in Case 1, and homozygous c.743 C>A in Case 2 (PMID:22410471)
• Analysis of fibroblast cell lines from 9 patients with SURF1 mutations revealed a 70% decrease of the COX complex content to be associated with 32-54% upregulation of respiratory chain complexes I, III and V and accumulation of Cox5a subunit. (PMID:22465034)
• Study identified 21 patients with clinical features of Leigh syndrome who are either homozygous or compound heterozygous for SURF1 mutations. (PMID:22488715)
• This study suggested that hypertrophic olivary degeneration on magnetic resonance imaging in mitochondrial syndromes associated with POLG and SURF1 mutations. (PMID:22729384)
• Mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth disease. (PMID:24027061)
• studies support the view that COX assembly is much more dependent on SURF1 in humans than in mice. (PMID:26804654)
• the MT-ATP6 and SURF1 gene screening in Tunisian patients affected with classical Leigh syndrome and the computational investigation of the effect of detected mutations on its structure and functions by clinical and bioinformatics analyses. (PMID:29481804)
• Role of SURF1 in etiology of Leigh syndrome in Slovakia. (PMID:29715184)
• SURF1 mutations may be associated with worse clinical outcome in Chinese patients with Leigh syndrome than other populations. (PMID:29933018)
• Novel p.P298L SURF1 mutation in thiamine deficient Leigh syndrome patients compromises cytochrome c oxidase activity. (PMID:32380162)
• Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. (PMID:33771987)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	surf1	ENSDARG00000003592
mus_musculus	Surf1	ENSMUSG00000015790
drosophila_melanogaster	Surf1	FBGN0029117
caenorhabditis_elegans		WBGENE00004787

Paralogs (1): SURF4 (ENSG00000148248)

Protein

Protein identifiers

Surfeit locus protein 1 — Q15526 (reviewed: Q15526)

All UniProt accessions (3): Q15526, A0A087WYS9, E5KRX5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.

Subunit / interactions. Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14. Interacts with COA3.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 1 (MC4DN1) [MIM:220110] An autosomal recessive disorder of the mitochondrial respiratory chain characterized by early-onset, rapidly progressive encephalopathy, neurodegeneration, and loss of motor and cognitive skills. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, poor eye contact, oculomotor abnormalities, as well as deafness, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia. Lactate levels in serum and cerebrospinal fluid are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death in childhood may occur, often due to central respiratory failure. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, demyelinating, type 4K (CMT4K) [MIM:616684] An autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus and late-onset cerebellar ataxia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SURF1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15526-1	1	yes
Q15526-2	2

RefSeq proteins (2): NP_001267716, NP_003163* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002994	Surf1/Shy1	Family
IPR045214	Surf1/Surf4	Family

Pfam: PF02104

UniProt features (24 total): sequence variant 20, transmembrane region 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15526-F1	82.62	0.65

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 253 (showing top): GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, HSIAO_HOUSEKEEPING_GENES, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, MODULE_307, GOCC_MITOCHONDRIAL_ENVELOPE, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, AFFAR_YY1_TARGETS_UP, WONG_MITOCHONDRIA_GENE_MODULE, GOBP_CELLULAR_RESPIRATION, KANNAN_TP53_TARGETS_UP

GO Biological Process (4): respiratory chain complex IV assembly (GO:0008535), aerobic respiration (GO:0009060), mitochondrial respiratory chain complex IV assembly (GO:0033617), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): cytochrome-c oxidase activity (GO:0004129), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex (GO:0098803), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Respiratory electron transport	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytochrome complex assembly	1
cellular respiration	1
mitochondrion	1
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
monoatomic cation transmembrane transport	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on a heme group of donors	1
active monoatomic ion transmembrane transporter activity	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SURF1	COX10	Q12887	963
SURF1	SURF2	Q15527	962
SURF1	COX15	Q7KZN9	961
SURF1	SCO2	O43819	956
SURF1	SCO1	O75880	948
SURF1	SURF4	O15260	887
SURF1	COA3	Q9Y2R0	877
SURF1	COX14	Q96I36	869
SURF1	TACO1	Q9BSH4	833
SURF1	MT-CO2	P00403	818
SURF1	OXA1L	Q15070	811
SURF1	MED22	Q15528	811
SURF1	COX17	Q14061	808
SURF1	COX6B1	P14854	808
SURF1	LRPPRC	P42704	800

IntAct

54 interactions, top by confidence:

A	B	Type	Score
TUBA1C	TXNDC9	psi-mi:“MI:0914”(association)	0.730
GBP5	GBP1	psi-mi:“MI:0914”(association)	0.720
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
SURF1	COA3	psi-mi:“MI:0915”(physical association)	0.560
IFNA5	IFNA13	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
SURF1	ACADVL	psi-mi:“MI:0915”(physical association)	0.400
PTGES3	SURF1	psi-mi:“MI:0915”(physical association)	0.370
MOSPD2	FLNA	psi-mi:“MI:0914”(association)	0.350
MGARP	BTAF1	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
MAGEA8	METTL15	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
AQP3	RTL8C	psi-mi:“MI:0914”(association)	0.350
EDEM2	HACD1	psi-mi:“MI:0914”(association)	0.350
GPR12	TLCD2	psi-mi:“MI:0914”(association)	0.350
COX4I1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
CDHR2	HIP1R	psi-mi:“MI:0914”(association)	0.350
LPCAT2	ADGRL1	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
AQP3	UBXN8	psi-mi:“MI:0914”(association)	0.350
IFNA5	LGALS9	psi-mi:“MI:0914”(association)	0.350
SYP	HAS3	psi-mi:“MI:0914”(association)	0.350
HYAL1	CDIPT	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B	SCAMP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (203): SURF1 (Affinity Capture-RNA), SURF1 (Affinity Capture-RNA), ACADVL (Affinity Capture-MS), SURF1 (Affinity Capture-MS), SURF1 (Affinity Capture-MS), ACADVL (Affinity Capture-MS), SURF1 (Affinity Capture-MS), SURF1 (Affinity Capture-MS), SURF1 (Affinity Capture-MS), ABCB7 (Proximity Label-MS), ACAD9 (Proximity Label-MS), ACADVL (Proximity Label-MS), ACOT1 (Proximity Label-MS), ACOT2 (Proximity Label-MS), AFG3L2 (Proximity Label-MS)

ESM2 similar proteins: A1A4L1, A1L1F1, A4IHH4, A4QP75, B8JMH0, D4A1F2, F1MF74, F1QWK4, F1RA39, O57593, O94851, P08574, P09925, P51687, Q08BI9, Q0P4Y8, Q0ZHH6, Q15526, Q32PX9, Q3B8B2, Q3SZV6, Q3V384, Q5EBA1, Q5RJV0, Q5SPH9, Q5XG58, Q5XKA2, Q60HD0, Q66LN0, Q6DD88, Q6DFN1, Q7ZU92, Q7ZWN0, Q800L1, Q80YD1, Q810S1, Q8BGB8, Q8BIP0, Q8BML1, Q8BWM0

Diamond homologs: A4IHH4, A8Y2C9, A9UWF0, O57593, P09925, Q15526, Q800L1, Q9N5N8, Q9QXU2, Q9SE51, Q9U4F3, Q9Y810, Q556J9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
YY1	“up-regulates quantity by expression”	SURF1	“transcriptional regulation”
MYC	“up-regulates quantity by expression”	SURF1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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
Complex IV assembly	8	31.5×	4e-08
Respiratory electron transport	6	9.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	47
Uncertain significance	208
Likely benign	329
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1182215	NM_003172.4(SURF1):c.367_368del (p.Arg123fs)	Pathogenic
12758	NM_003172.4(SURF1):c.323+2T>C	Pathogenic
12762	NM_003172.4(SURF1):c.751C>T (p.Gln251Ter)	Pathogenic
12764	NM_003172.4(SURF1):c.515+2T>G	Pathogenic
12765	NM_003172.4(SURF1):c.550_551del (p.Arg184fs)	Pathogenic
12766	NM_003172.4(SURF1):c.820T>G (p.Tyr274Asp)	Pathogenic
12768	NM_003172.4(SURF1):c.371G>A (p.Gly124Glu)	Pathogenic
12769	NM_003172.4(SURF1):c.574_575insCTCC (p.Arg192fs)	Pathogenic
12770	NM_003172.4(SURF1):c.845_846del (p.Ser282fs)	Pathogenic
1320126	NM_003172.4(SURF1):c.595_598del (p.Gly199fs)	Pathogenic
1320241	NM_003172.4(SURF1):c.283del (p.Glu95fs)	Pathogenic
1321366	NM_003172.4(SURF1):c.867G>A (p.Trp289Ter)	Pathogenic
1323661	NM_003172.4(SURF1):c.815_818dup (p.Gln273fs)	Pathogenic
1323662	NM_003172.4(SURF1):c.152dup (p.Ser52fs)	Pathogenic
1363063	NM_003172.4(SURF1):c.577C>T (p.Gln193Ter)	Pathogenic
1386019	NM_003172.4(SURF1):c.266_271del (p.Asn89_Leu90del)	Pathogenic
1388760	NM_003172.4(SURF1):c.273del (p.Ile91fs)	Pathogenic
1397724	NM_003172.4(SURF1):c.58_59dup (p.Ala21fs)	Pathogenic
1416074	NM_003172.4(SURF1):c.552del (p.Lys185fs)	Pathogenic
1451209	NM_003172.4(SURF1):c.485_486del (p.Val162fs)	Pathogenic
1453626	NM_003172.4(SURF1):c.19_35del (p.Leu7fs)	Pathogenic
1459173	NM_003172.4(SURF1):c.773_784del (p.Pro258_Gly261del)	Pathogenic
1705227	NM_003172.4(SURF1):c.773_774del (p.Pro258fs)	Pathogenic
1993665	NM_003172.4(SURF1):c.581_582del (p.Lys194fs)	Pathogenic
2081237	NM_003172.4(SURF1):c.751+1G>A	Pathogenic
2136829	NM_003172.4(SURF1):c.589-1G>C	Pathogenic
2136830	NM_003172.4(SURF1):c.19_35dup (p.Ala13fs)	Pathogenic
2152072	NC_000009.12:g.133352139CT[1]	Pathogenic
215236	NM_003172.4(SURF1):c.589-1G>T	Pathogenic
215237	NM_003172.4(SURF1):c.312_321delinsAT (p.Pro104_Leu105insTer)	Pathogenic

SpliceAI

1150 predictions. Top by Δscore:

Variant	Effect	Δscore
9:133352413:A:AC	donor_gain	1.0000
9:133352414:C:CC	donor_gain	1.0000
9:133352444:A:AC	donor_gain	1.0000
9:133352445:C:CC	donor_gain	1.0000
9:133354657:A:AC	donor_gain	1.0000
9:133354658:C:CC	donor_gain	1.0000
9:133354658:CT:C	donor_gain	1.0000
9:133354658:CTCGG:C	donor_gain	1.0000
9:133351982:CCTAG:C	acceptor_loss	0.9900
9:133351983:CTA:C	acceptor_loss	0.9900
9:133351984:T:C	acceptor_loss	0.9900
9:133351990:T:C	acceptor_gain	0.9900
9:133352139:CTCT:C	acceptor_gain	0.9900
9:133352605:CAAT:C	acceptor_gain	0.9900
9:133352609:C:CC	acceptor_gain	0.9900
9:133352765:CT:C	acceptor_gain	0.9900
9:133352767:C:CC	acceptor_gain	0.9900
9:133353747:ACC:A	donor_gain	0.9900
9:133353748:CCC:C	donor_gain	0.9900
9:133353936:TTGGG:T	acceptor_gain	0.9900
9:133353941:C:CC	acceptor_gain	0.9900
9:133356659:G:GT	donor_gain	0.9900
9:133356671:G:GG	donor_gain	0.9900
9:133351989:G:C	acceptor_gain	0.9800
9:133351989:G:GC	acceptor_gain	0.9800
9:133352143:C:CC	acceptor_gain	0.9800
9:133352445:CGGAA:C	donor_gain	0.9800
9:133353387:C:CA	donor_gain	0.9800
9:133353747:AC:A	donor_gain	0.9800
9:133353748:CC:C	donor_gain	0.9800

AlphaMissense

1926 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:133352737:A:T	V182D	0.996
9:133354721:C:A	K87N	0.996
9:133354721:C:G	K87N	0.996
9:133352062:A:G	W278R	0.994
9:133352062:A:T	W278R	0.994
9:133352743:C:T	G180E	0.994
9:133354731:C:G	R84P	0.994
9:133352739:G:C	F181L	0.992
9:133352739:G:T	F181L	0.992
9:133352741:A:G	F181L	0.992
9:133354734:C:G	R83P	0.991
9:133352744:C:G	G180R	0.990
9:133352744:C:T	G180R	0.990
9:133354722:T:G	K87T	0.990
9:133352583:C:T	G205E	0.989
9:133352744:C:A	G180W	0.989
9:133354713:A:G	L90P	0.989
9:133354824:C:A	Q80H	0.989
9:133354824:C:G	Q80H	0.989
9:133352745:T:A	R179S	0.988
9:133352745:T:G	R179S	0.988
9:133354723:T:C	K87E	0.988
9:133352752:A:T	V177E	0.987
9:133353893:C:T	G124E	0.987
9:133354735:G:T	R83S	0.987
9:133352584:C:A	G205W	0.985
9:133352743:C:A	G180V	0.985
9:133354834:C:T	G77E	0.985
9:133352081:A:C	H271Q	0.984
9:133352081:A:T	H271Q	0.984

dbSNP variants (sampled 300 via entrez): RS1000122661 (9:133355514 G>A,C), RS1000309002 (9:133355335 C>CCAA), RS1000459492 (9:133356575 T>C), RS1000578270 (9:133356680 G>A), RS1000690252 (9:133355782 C>T), RS1000904633 (9:133354222 T>C), RS1000971325 (9:133354645 A>C), RS1001525942 (9:133351289 C>T), RS1001583495 (9:133356484 G>A,C), RS1001790829 (9:133356106 T>G), RS1001895310 (9:133357182 G>A), RS1001967979 (9:133352285 C>T), RS1002014545 (9:133356610 C>A,G,T), RS1002114837 (9:133356925 C>A,T), RS1002251672 (9:133352188 C>G,T)

Disease associations

OMIM: gene MIM:185620 | disease phenotypes: MIM:256000, MIM:616684, MIM:220110, MIM:615119

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 1	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease type 4K	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
Leigh syndrome with cardiomyopathy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (8): Leigh syndrome (MONDO:0009723), Charcot-Marie-Tooth disease type 4K (MONDO:0014733), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), mitochondrial disease (MONDO:0044970), cerebellar ataxia (MONDO:0000437), cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (MONDO:0014051), (MONDO:0016815), Leigh syndrome with cardiomyopathy (MONDO:0019083)

Orphanet (5): Leigh syndrome (Orphanet:506), SURF1-related Charcot-Marie-Tooth disease type 4 (Orphanet:391351), Mitochondrial disease (Orphanet:68380), Rare ataxia (Orphanet:102002), Fatal infantile cytochrome C oxidase deficiency (Orphanet:1561)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001348	Brisk reflexes
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:0002078	Truncal ataxia
HP:0002098	Respiratory distress

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST009541_8	Heart failure	4.000000e-09
GCST010725_19	Malaria	9.000000e-11
GCST010725_31	Malaria	9.000000e-21
GCST010725_98	Malaria	1.000000e-19

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
jinfukang	increases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	decreases expression	1
Cisplatin	increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	decreases expression	1
Phthalic Acids	increases methylation	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Thapsigargin	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

35 cell lines: 29 finite cell line, 3 cancer cell line, 2 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2YP	GM28010	Finite cell line	Male
CVCL_A2YQ	GM28011	Finite cell line	Female
CVCL_A2YR	GM28012	Finite cell line	Female
CVCL_A2YS	GM28013	Finite cell line	Female
CVCL_A2YT	GM28014	Finite cell line	Female
CVCL_A2YU	GM28016	Finite cell line	Male
CVCL_A2YV	GM28017	Finite cell line	Female
CVCL_A5MA	GM28019	Finite cell line	Female
CVCL_A5MB	GM28020	Finite cell line	Male
CVCL_A5MC	GM28021	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
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)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)