SDHAF2

Chr 11AD

succinate dehydrogenase complex assembly factor 2

NCBI Gene: 54949ENSG00000167985UniProt: Q9NX18

Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer

Primary Disease Associations & Inheritance

Pheochromocytoma/paraganglioma syndrome 2MIM #601650
AD
543
ClinVar variants
42
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SDHAF2
🧬
Gene-Disease Validity (ClinGen)
hereditary pheochromocytoma-paraganglioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 307 VUS of 543 total submissions

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.
1.81LOEUF
pLI 0.000
Z-score -0.28
OE 1.11 (0.65–1.81)
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.
-0.14Z-score
OE missense 1.04 (0.88–1.24)
92 obs / 88.3 exp
Tolerant

Tolerant to missense variation

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 (0.65–1.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.88–1.24)
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.1.17
0≤1.21.6
LoF obs/exp: 8 / 7.2Missense obs/exp: 92 / 88.3Syn Z: -0.75

ClinVar Variant Classifications

543 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic25
VUS307
Likely Benign154
Benign7
Conflicting33
17
Pathogenic
25
Likely Pathogenic
307
VUS
154
Likely Benign
7
Benign
33
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
1
9
0
17
Likely Pathogenic
16
1
8
0
25
VUS
16
239
45
7
307
Likely Benign
0
5
58
91
154
Benign
0
0
7
0
7
Conflicting
—33
Total3924612798543

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

View in ClinVar →

Protein Context — Lollipop Plot

SDHAF2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SDHAF2-related paragangliomas

definitive
ADUndeterminedAltered Gene Product Structure
Cancer
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pheochromocytoma/paraganglioma syndrome 2

MIM #601650

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SDHAF2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
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
New Insights into the Clinical Characterization of SDHAF2-related Familial Paraganglioma Syndrome.
Fernandez-Pombo A et al.·J Clin Endocrinol Metab
2025
SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma.
Bayley JP et al.·Lancet Oncol
2010
Hereditary succinate dehydrogenase-deficient renal cell carcinoma.
Rogala J et al.·Semin Diagn Pathol
2024Review
Update on Tumor Surveillance for Children with Hereditary Pheochromocytoma/Paraganglioma Syndromes.
Rednam SP et al.·Clin Cancer Res
2025Review
Pathology and genetics of phaeochromocytoma and paraganglioma.
Turchini J et al.·Histopathology
2018Review
SDH mutations in cancer.
Bardella C et al.·Biochim Biophys Acta
2011Review
Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas.
Kugelberg J et al.·World J Surg
2014
Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas.
Welander J et al.·Endocr Relat 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