SDHD

Chr 11ARAD

succinate dehydrogenase complex subunit D

Also known as: CBT1, CII-4, CWS3, MC2DN3, PGL, PGL1, PPGL1, QPs3

NCBI Gene: 6392ENSG00000204370UniProt: O14521

This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

Primary Disease Associations & Inheritance

Mitochondrial complex II deficiency, nuclear type 3MIM #619167
AR
Paraganglioma and gastric stromal sarcomaMIM #606864
Pheochromocytoma/paraganglioma syndrome 1MIM #168000
AD
595
ClinVar variants
99
Pathogenic / LP
0.34
pLI score
0
Active trials
Clinical Summary— SDHD
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 285 VUS of 595 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.
0.73LOEUF
pLI 0.337
Z-score 2.09
OE 0.23 (0.09–0.73)
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.
-0.17Z-score
OE missense 1.05 (0.89–1.25)
90 obs / 85.7 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.0.23 (0.09–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.89–1.25)
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.0.84
0≤1.21.6
LoF obs/exp: 2 / 8.6Missense obs/exp: 90 / 85.7Syn Z: 0.75

ClinVar Variant Classifications

595 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic31
VUS285
Likely Benign168
Benign23
Conflicting20
68
Pathogenic
31
Likely Pathogenic
285
VUS
168
Likely Benign
23
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
3
32
0
68
Likely Pathogenic
20
4
7
0
31
VUS
6
241
36
2
285
Likely Benign
0
20
69
79
168
Benign
0
6
11
6
23
Conflicting
—20
Total5927415587595

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

View in ClinVar →

Protein Context — Lollipop Plot

SDHD · protein map & ClinVar variants

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

Gene2Phenotype Curations

SDHD-related pheochromocytoma

definitive
ADGain Of FunctionAltered Gene Product Structure
Skin
G2P ↗

SDHD-related carcinoid tumors, intestinal

limited
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗
missense variantinframe deletioninframe insertion

SDHD-related paragangliomas with or without deafness

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

Mitochondrial complex II deficiency, nuclear type 3

MIM #619167

Molecular basis of disorder known

Autosomal recessive

Paraganglioma and gastric stromal sarcoma

MIM #606864

Molecular basis of disorder known

Pheochromocytoma/paraganglioma syndrome 1

MIM #168000

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SDHD
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.
Taïeb D et al.·Lancet Diabetes Endocrinol
2023Review
International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.
Amar L et al.·Nat Rev Endocrinol
2021Review
Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.
Muth A et al.·J Intern Med
2019Review
Oncometabolites suppress DNA repair by disrupting local chromatin signalling.
Sulkowski PL et al.·Nature
2020
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
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
Garrett A et al.·Genet Med
2022
Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.
Han G et al.·Cell Stem Cell
2024
Phaeochromocytoma: state-of-the-art.
Donckier JE et al.·Acta Chir Belg
2010Review
Familial nonsyndromic pheochromocytoma.
Opocher G et al.·Ann N Y Acad Sci
2006
SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.
Bayley JP et al.·J Med Genet
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
An Unusual High-Grade Sarcoma of the Kidney with TPM4::NTRK1 Fusion, CDKN2A/B Deletion, SDHD and NOTCH3 Variants: The First Case Report in Pediatric Population.
Wei X et al.·Fetal Pediatr Pathol
2026Case report
A Novel Targeted Sequence for Chromosome 11p15.5 Maternal Loss in SDHD-Related Paragangliomas.
Lai HP et al.·Genes Chromosomes Cancer
2026
Heterozygous mutation in the SdhD subunit confers resistance to thifluzamide in the multinucleate pathogen Sclerotium rolfsii.
Jiang C et al.·Pest Manag Sci
2026
In vivo and in vitro analysis of functional effects of the SDHD H50R variant.
Priya S et al.·Endocr Relat Cancer
2025Functional
Identification of a pathogenic SDHD mutation in a Chinese family with hereditary head and neck paraganglioma: implications for genetic counseling and management.
Wang P et al.·World J Surg Oncol
2025🔓 Open Access
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