SDHB

Chr 1ADIsolated casesAR

succinate dehydrogenase complex iron sulfur subunit B

Also known as: CWS2, IP, MC2DN4, PGL4, PPGL4, SDH, SDH1, SDH2

NCBI Gene: 6390ENSG00000117118UniProt: P21912

This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

Primary Disease Associations & Inheritance

Gastrointestinal stromal tumorMIM #606764
ADIsolated cases
Mitochondrial complex II deficiency, nuclear type 4MIM #619224
AR
Paraganglioma and gastric stromal sarcomaMIM #606864
Pheochromocytoma/paraganglioma syndrome 4MIM #115310
AD
586
ClinVar variants
88
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SDHB
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · 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
88 Pathogenic / Likely Pathogenic· 276 VUS of 586 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.82LOEUF
pLI 0.000
Z-score 2.13
OE 0.47 (0.28–0.82)
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.
-0.10Z-score
OE missense 1.02 (0.90–1.17)
158 obs / 154.4 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.0.47 (0.28–0.82)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.02 (0.90–1.17)
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.1.00
0≤1.21.6
LoF obs/exp: 9 / 19.0Missense obs/exp: 158 / 154.4Syn Z: 0.02

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic29
VUS276
Likely Benign188
Benign20
Conflicting14
59
Pathogenic
29
Likely Pathogenic
276
VUS
188
Likely Benign
20
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
34
3
22
0
59
Likely Pathogenic
13
9
7
0
29
VUS
2
231
41
2
276
Likely Benign
0
2
109
77
188
Benign
0
0
6
14
20
Conflicting
—14
Total4924518593586

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

View in ClinVar →

Protein Context — Lollipop Plot

SDHB · protein map & ClinVar variants

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

Gene2Phenotype Curations

SDHB-related pheochromocytoma

definitive
ADGain Of FunctionAltered Gene Product Structure
Skin
G2P ↗

SDHB-related gastrointestinal stromal tumor

definitive
ADLoss Of FunctionAbsent Gene Product
SkinCancer
G2P ↗

SDHB-related paraganglioma and gastric stromal sarcoma

definitive
ADLoss Of FunctionAbsent Gene Product
SkinCancer
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Gastrointestinal stromal tumor

MIM #606764

Molecular basis of disorder known

Autosomal dominantIsolated cases

Mitochondrial complex II deficiency, nuclear type 4

MIM #619224

Molecular basis of disorder known

Autosomal recessive

Paraganglioma and gastric stromal sarcoma

MIM #606864

Molecular basis of disorder known

Pheochromocytoma/paraganglioma syndrome 4

MIM #115310

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SDHB
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Metabolic Basis of Kidney Cancer.
Linehan WM et al.·Cancer Discov
2019Review
Succinate preserves CD8(+) T cell fitness to augment antitumor immunity.
Ma K et al.·Immunity
2025
International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.
Amar L et al.·Nat Rev Endocrinol
2021Review
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.
Kim J et al.·JNCI Cancer Spectr
2021
Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.
Muth A et al.·J Intern Med
2019Review
Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.
Taïeb D et al.·Nat Rev Endocrinol
2024Review
Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.
Andrews KA et al.·J Med Genet
2018
Metastatic paraganglioma.
Fliedner SM et al.·Semin Oncol
2010Review
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
Garrett A et al.·Genet Med
2022
Outcomes of SDHB Pathogenic Variant Carriers.
Davidoff DF et al.·J Clin Endocrinol Metab
2024Meta-analysis
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
Von Hippel-Lindau DiseaseHereditary Leiomyomatosis and Renal Cell CancerBirt-Hogg-Dube Syndrome

MyVHL: Patient Natural History Study

RECRUITING
NCT03749980Joshua Mann, MPHStarted 2012-01

External Resources

Links to major genomics databases and tools