SDHD

Chr 11ARAD

succinate dehydrogenase complex subunit D

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

NCBI Gene: 6392 ENSG00000204370 OMIM: 602690

The SDHD protein is a membrane-anchoring subunit of succinate dehydrogenase (complex II) that transfers electrons from succinate to ubiquinone in the mitochondrial electron transport chain. Mutations cause mitochondrial complex II deficiency (autosomal recessive inheritance) and pheochromocytoma/paraganglioma syndrome (autosomal dominant inheritance with paternal imprinting, meaning disease transmission occurs almost exclusively through the paternal allele). Loss of SDHD function leads to impaired cellular respiration and tumor formation through disrupted mitochondrial metabolism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.733 OMIM phenotypes

Clinical Summary— SDHD

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

172 unique Pathogenic / Likely Pathogenic· 426 VUS of 936 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SDHD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.337

Z-score 2.09

OE 0.23 (0.09–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.17Z-score

OE missense 1.05 (0.89–1.25)

90 obs / 85.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.23 (0.09–0.73)

0≤0.351.4

Missense OE?1.05 (0.89–1.25)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 2 / 8.6Missense obs/exp: 90 / 85.7Syn Z: 0.75

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSDHD-related pheochromocytomaGOFAD

limitedSDHD-related carcinoid tumors, intestinalOTHERAD

definitiveSDHD-related paragangliomas with or without deafnessLOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.5954th %ile

LOF

0.3067th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 69% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFMutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 10657297 ↗

ClinVar Variant Classifications

936 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic109

Likely Pathogenic63

VUS426

Likely Benign253

Benign28

Conflicting52

109

Pathogenic

Likely Pathogenic

426

VUS

253

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	79	12	18	0	109
Likely Pathogenic	39	20	4	0	63
VUS	15	362	47	2	426
Likely Benign	1	29	107	116	253
Benign	0	6	16	6	28
Conflicting	—				52
Total	134	429	192	124	931

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap SDHD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →