Hereditary pheochromocytoma and paraganglioma: genes and variants

Genes linked to Hereditary pheochromocytoma and paraganglioma

• TMEM127: Transmembrane protein 127

  It restrains growth signaling and participates in endomembrane trafficking, including regulation of mTOR-related pathways. Germline loss-of-function variants predispose primarily to pheochromocytoma and paraganglioma and can also occur in selected renal tumors.

  5 disease-causing and 360 uncertain variants in TMEM127 are linked to Hereditary pheochromocytoma and paraganglioma.

• SDHAF2: Succinate dehydrogenase assembly factor 2, mitochondrial

  It is required for covalent flavin attachment and maturation of the SDHA catalytic subunit, enabling normal succinate dehydrogenase activity. Germline loss-of-function variants can predispose to hereditary head-and-neck paragangliomas through functional loss of complex II.

  1 disease-causing and 230 uncertain variants in SDHAF2 are linked to Hereditary pheochromocytoma and paraganglioma.

• MAX: Protein max

  It forms DNA-binding dimers with MYC-family proteins and other partners, balancing transcriptional programs that promote or restrain proliferation. Germline loss-of-function variants predispose to pheochromocytoma and paraganglioma, while altered MAX-MYC signaling is central to many cancers.

  1 disease-causing and 153 uncertain variants in MAX are linked to Hereditary pheochromocytoma and paraganglioma.

• SDHC: Succinate dehydrogenase cytochrome b560 subunit, mitochondrial

  It anchors succinate dehydrogenase to the inner mitochondrial membrane and helps transfer electrons from the catalytic subunits to ubiquinone. Heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and some gastrointestinal stromal tumors.

  1 disease-causing and 40 uncertain variants in SDHC are linked to Hereditary pheochromocytoma and paraganglioma.

• SDHB: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial

  It transfers electrons from succinate oxidation through iron-sulfur centers toward ubiquinone in mitochondrial complex II. Heterozygous loss-of-function variants strongly predispose to paraganglioma and pheochromocytoma and can also increase renal-tumor and gastrointestinal-stromal-tumor risk.

  1 disease-causing and 43 uncertain variants in SDHB are linked to Hereditary pheochromocytoma and paraganglioma.

• SDHD: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial

  It provides a membrane-anchoring component of succinate dehydrogenase and is required for normal complex II electron transfer. Germline loss-of-function variants, often showing a parent-of-origin effect, strongly predispose to head-and-neck paragangliomas and pheochromocytomas.

  0 disease-causing and 19 uncertain variants in SDHD are linked to Hereditary pheochromocytoma and paraganglioma.

• SDHA: Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial

  It catalyzes oxidation of succinate to fumarate while transferring electrons into respiratory-chain complex II, directly linking the TCA cycle with oxidative phosphorylation. Biallelic deficiency can cause mitochondrial disease, while heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and selected gastrointestinal stromal tumors.

  0 disease-causing and 5 uncertain variants in SDHA are linked to Hereditary pheochromocytoma and paraganglioma.

Weakly linked (only a few uncertain records): DNMT3A.

Known disease-causing variants in Hereditary pheochromocytoma and paraganglioma

Which prediction tools work for Hereditary pheochromocytoma and paraganglioma

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MutPred2: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 99 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 67 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Gastrointestinal stromal tumor is also caused by SDHC variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (16 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHC variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (16 disease-causing).
• Gastrointestinal stromal tumor is also caused by SDHB variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (53 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHB variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (48 disease-causing).
• Pheochromocytoma is also caused by SDHB variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (47 disease-causing).
• Carney-Stratakis syndrome is also caused by SDHB variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (7 disease-causing).
• Mitochondrial complex 2 deficiency, nuclear type 3 is also caused by SDHB variants; they fall mostly in different places as the Hereditary pheochromocytoma and paraganglioma variants (7 disease-causing).

Diseases related to Hereditary pheochromocytoma and paraganglioma

• Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHA, SDHAF2, SDHB, SDHC and 1 more
• Pheochromocytoma, also linked to MAX, SDHB, SDHD and TMEM127
• Gastrointestinal stromal tumor, also linked to SDHA, SDHB and SDHC
• Carney-Stratakis syndrome, also linked to SDHB, SDHC and SDHD
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to SDHA, SDHB and SDHC
• Mitochondrial complex II deficiency, nuclear type 1, also linked to SDHA and SDHD
• Mitochondrial complex 2 deficiency, nuclear type 3, also linked to SDHB and SDHD
• Cowden syndrome, also linked to SDHD
• Paragangliomas with sensorineural hearing loss, also linked to SDHD
• Neurodegeneration with ataxia and late-onset optic atrophy, also linked to SDHA
• Familial isolated dilated cardiomyopathy, also linked to SDHA
• Dilated cardiomyopathy 1GG, also linked to SDHA

Frequently asked questions

Which genes are linked to Hereditary pheochromocytoma and paraganglioma?

In CATVariant, Hereditary pheochromocytoma and paraganglioma is linked to 7 analyzed proteins: TMEM127 (Transmembrane protein 127), SDHAF2 (Succinate dehydrogenase assembly factor 2, mitochondrial), MAX (Protein max), SDHC (Succinate dehydrogenase cytochrome b560 subunit, mitochondrial), SDHB (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial), SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial) and 1 more.

How many genetic variants are linked to Hereditary pheochromocytoma and paraganglioma?

866 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 852 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary pheochromocytoma and paraganglioma look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hereditary pheochromocytoma and paraganglioma?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 9 disease-causing and 42 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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