SDHA

Chr 5ARAD

succinate dehydrogenase complex flavoprotein subunit A

Also known as: CMD1GG, FP, MC2DN1, NDAXOA, PGL5, PPGL5, SDH1, SDH2

NCBI Gene: 6389ENSG00000073578UniProt: P31040

This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1GGMIM #613642
AR
Mitochondrial complex II deficiency, nuclear type 1MIM #252011
AR
Neurodegeneration with ataxia and late-onset optic atrophyMIM #619259
AD
Pheochromocytoma/paraganglioma syndrome 5MIM #614165
AD
UniProtLeigh syndrome
482
ClinVar variants
64
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SDHA
🧬
Gene-Disease Validity (ClinGen)
hereditary pheochromocytoma-paraganglioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

4 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
64 Pathogenic / Likely Pathogenic· 258 VUS of 482 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

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

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.
0.86LOEUF
pLI 0.000
Z-score 2.22
OE 0.60 (0.42–0.86)
Tolerant

Typical tolerance to LoF variation

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.
0.74Z-score
OE missense 0.89 (0.82–0.98)
346 obs / 387.3 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.0.60 (0.42–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.82–0.98)
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.1.14
0≤1.21.6
LoF obs/exp: 21 / 35.2Missense obs/exp: 346 / 387.3Syn Z: -1.41

ClinVar Variant Classifications

482 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic25
VUS258
Likely Benign125
Benign25
Conflicting10
39
Pathogenic
25
Likely Pathogenic
258
VUS
125
Likely Benign
25
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
0
14
0
39
Likely Pathogenic
20
1
4
0
25
VUS
5
219
32
2
258
Likely Benign
0
0
58
67
125
Benign
0
0
4
21
25
Conflicting
—10
Total5022011290482

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

View in ClinVar →

Protein Context — Lollipop Plot

SDHA · protein map & ClinVar variants

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

Gene2Phenotype Curations

SDHA-related paragangliomas

definitive
ADLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

SDHA-related Leigh syndrome

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 Relationships

1 OMIM entry

OMIM

Cardiomyopathy, dilated, 1GG

MIM #613642

Molecular basis of disorder known

Autosomal recessive

Mitochondrial complex II deficiency, nuclear type 1

MIM #252011

Molecular basis of disorder known

Autosomal recessive

Neurodegeneration with ataxia and late-onset optic atrophy

MIM #619259

Molecular basis of disorder known

Autosomal dominant

Pheochromocytoma/paraganglioma syndrome 5

MIM #614165

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SDHA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic Germline Variants in 10,389 Adult Cancers.
Huang KL et al.·Cell
2018
International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.
Amar L et al.·Nat Rev Endocrinol
2021Review
UK recommendations for SDHA germline genetic testing and surveillance in clinical practice.
Hanson H et al.·J Med Genet
2023
Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.
Muth A et al.·J Intern Med
2019Review
Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.
Bausch B et al.·JAMA Oncol
2017
Oncometabolites suppress DNA repair by disrupting local chromatin signalling.
Sulkowski PL et al.·Nature
2020
SDHA-related phaeochromocytoma and paraganglioma: review and clinical management.
Kaplan AI et al.·Endocr Relat Cancer
2024Review
Identification and validation of extracellular vesicle reference genes for the normalization of RT-qPCR data.
Pinheiro C et al.·J Extracell Vesicles
2024
SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update.
Schipani A et al.·Genes (Basel)
2023Review
Epidemiology of Renal Cancer: Incidence, Mortality, Survival, Genetic Predisposition, and Risk Factors.
Larcher A et al.·Eur Urol
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Comprehensive analysis of germline and somatic SDHA alterations reveals rare incidental germline variants and prognostic implications of somatic loss in breast cancer.
Butz H et al.·Endocr Relat Cancer
2026
To screen or not to screen: complexity of SDHA mutation management.
Mohamed E et al.·Endocr Oncol
2026🔓 Open Access
SDHA Deficiency in Hepatocellular Carcinoma Promotes Tumor Progression through Succinate-Induced M2 Macrophage Polarization.
Li X et al.·Oncol Res
2026🔓 Open Access
EPAS1 increases SDHA to inhibit proliferation of multiple myeloma cells by restoring TCA Cycle.
Sun Y et al.·NPJ Precis Oncol
2025🔓 Open Access
Structure and expression kinetics of Piscirickettsia salmonis sdhA during infection of Atlantic salmon macrophage-like cells.
Cortés M et al.·Fish Shellfish Immunol
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rheumatoid ArthritisOsteoarthritisSarcopenia

Effect of Exercise Type on Muscle Quality in Patients With OA, SARC and RA: an Explorative Study

NOT YET RECRUITING
NCT06480643Phase NAAmsterdam UMC, location VUmcStarted 2024-12-01
High load exercise typeLow load exercise type

External Resources

Links to major genomics databases and tools