SURF1

Chr 9AR

SURF1 cytochrome c oxidase assembly factor

Also known as: CMT4K, MC4DN1, SHY1

NCBI Gene: 6834 ENSG00000148290 UniProt: Q15526 OMIM: 185620

The SURF1 protein localizes to the inner mitochondrial membrane and is involved in the biogenesis of cytochrome c oxidase (complex IV). Mutations cause autosomal recessive mitochondrial complex IV deficiency leading to Leigh syndrome and Charcot-Marie-Tooth disease type 4K through loss of function. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern where biallelic mutations are required for disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.722 OMIM phenotypes

Clinical Summary— SURF1

🧬

Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

179 unique Pathogenic / Likely Pathogenic· 214 VUS of 817 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SURF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.72LOEUF

pLI 0.000

Z-score -0.67

OE 1.19 (0.82–1.72)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.68Z-score

OE missense 1.15 (1.02–1.31)

177 obs / 153.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.19 (0.82–1.72)

0≤0.351.4

Missense OE?1.15 (1.02–1.31)

0≤0.61.4

Synonymous OE?1.65

0≤1.21.6

LoF obs/exp: 18 / 15.2Missense obs/exp: 177 / 153.3Syn Z: -3.89

ClinVar Variant Classifications

817 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic98

Likely Pathogenic81

VUS214

Likely Benign360

Benign23

Conflicting32

Pathogenic

Likely Pathogenic

214

VUS

360

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	81	13	3	1	98
Likely Pathogenic	53	23	5	0	81
VUS	4	192	15	3	214
Likely Benign	0	3	184	173	360
Benign	0	1	22	0	23
Conflicting	—				32
Total	138	232	229	177	808

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

37 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap SURF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →