SDHAF1

Chr 19

succinate dehydrogenase complex assembly factor 1

Also known as: LYRM8, MC2DN2

NCBI Gene: 644096ENSG00000205138UniProt: A6NFY7

The succinate dehydrogenase (SDH) complex (or complex II) of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by this gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo. Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy (mitochondrial complex II deficiency).[provided by RefSeq, Mar 2010]

Primary Disease Associations & Inheritance

UniProtMitochondrial complex II deficiency, nuclear type 2
107
ClinVar variants
19
Pathogenic / LP
0.09
pLI score
0
Active trials
Clinical Summary— SDHAF1
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.09) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 61 VUS of 107 total submissions
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.90LOEUF
pLI 0.087
Z-score -0.09
OE 1.11 (0.28–1.90)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.38Z-score
OE missense 0.86 (0.68–1.09)
49 obs / 57.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.11 (0.28–1.90)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.68–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.77
0≤1.21.6
LoF obs/exp: 1 / 0.9Missense obs/exp: 49 / 57.1Syn Z: 0.94

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic3
VUS61
Likely Benign20
Benign4
Conflicting3
16
Pathogenic
3
Likely Pathogenic
61
VUS
20
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
13
0
16
Likely Pathogenic
0
1
2
0
3
VUS
0
43
17
1
61
Likely Benign
0
1
4
15
20
Benign
0
1
3
0
4
Conflicting
—3
Total0493916107

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

View in ClinVar →

Protein Context — Lollipop Plot

SDHAF1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SDHAF1-related mitochondrial complex II deficiency

definitive
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The genetic basis of isolated mitochondrial complex II deficiency.
Fullerton M et al.·Mol Genet Metab
2020Review
The role of complex II in disease.
Hoekstra AS et al.·Biochim Biophys Acta
2013Review
Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB.
Maio N et al.·Cell Metab
2016
Genetic associations with dementia-related proteinopathy: Application of item response theory.
Katsumata Y et al.·Alzheimers Dement
2024
Complex II deficiency--a case report and review of the literature.
Jain-Ghai S et al.·Am J Med Genet A
2013Review
A variant of uncertain significance in SDHAF1, the succinate dehydrogenase chaperone protein, in an adult patient with spastic paraparesis and leukoencephalopathy.
Vlahovic L et al.·Mult Scler Relat Disord
2021Case report
Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy.
Helman G et al.·Ann Neurol
2016
[Mitochondrial respiratory chain complex Ⅱ deficiency and diseases].
Ma YY et al.·Zhongguo Dang Dai Er Ke Za Zhi
2012Review
Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency.
Ohlenbusch A et al.·Orphanet J Rare Dis
2012
Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma.
Hensen EF et al.·Fam Cancer
2011Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools