Inherited phaeochromocytoma and paraganglioma excluding NF1: genes and variants
Inherited phaeochromocytoma and paraganglioma excluding NF1 is linked to 5 analyzed proteins (SDHB, VHL, SDHC, SDHA and FH). 10 DNA variants are known to cause it; 6 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Inherited phaeochromocytoma and paraganglioma excluding NF1
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.
4 disease-causing and 0 uncertain variants in SDHB are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1.
VHL: von Hippel-Lindau disease tumor suppressor
It targets hydroxylated HIF-alpha proteins for ubiquitin-mediated degradation when oxygen is sufficient, keeping hypoxia-response programs suppressed. Loss of function stabilizes HIF signaling and causes von Hippel-Lindau tumor-predisposition syndrome while also driving most clear-cell renal carcinomas.
2 disease-causing and 1 uncertain variants in VHL are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1.
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.
2 disease-causing and 0 uncertain variants in SDHC are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1.
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.
1 disease-causing and 2 uncertain variants in SDHA are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1.
FH: Fumarate hydratase, mitochondrial
It converts fumarate to malate in the mitochondrial TCA cycle. Biallelic loss causes fumarase deficiency, while heterozygous loss-of-function variants cause hereditary leiomyomatosis and renal cell cancer syndrome through fumarate accumulation and tumor-suppressor loss.
1 disease-causing and 1 uncertain variants in FH are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1.
Weakly linked (only a few uncertain records): SDHAF2 and SDHD.
Known disease-causing variants in Inherited phaeochromocytoma and paraganglioma excluding NF1
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| SDHB K40E | 40 | 2Fe-2S ferredoxin-type | Disease-causing (★★) |
| SDHB G96S | 96 | 2Fe-2S ferredoxin-type | Disease-causing (★★) |
| SDHC Y126C | 126 | Transmembrane | Disease-causing (★★) |
| SDHC H127R | 127 | Transmembrane | Disease-causing (★★) |
| SDHA R589W | 589 | Disease-causing (★★) | |
| FH F312L | 312 | Disease-causing (★★) | |
| VHL R161Q | 161 | Interaction with Elongin BC complex | Disease-causing (★★) |
| SDHB C98R | 98 | 2Fe-2S ferredoxin-type | Disease-causing (★★) |
| VHL P81L | 81 | Disease-causing (★★) | |
| SDHB N104S | 104 | 2Fe-2S ferredoxin-type | Disease-causing (★) |
Which prediction tools work for Inherited phaeochromocytoma and paraganglioma excluding NF1
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 93 out of 100
- SIFT: 92 out of 100
- phyloP: 85 out of 100
Same protein, different disease
- Gastrointestinal stromal tumor is also caused by SDHB variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (53 disease-causing).
- Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHB variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (48 disease-causing).
- Pheochromocytoma is also caused by SDHB variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (47 disease-causing).
- Carney-Stratakis syndrome is also caused by SDHB variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 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 Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (7 disease-causing).
- Von Hippel-Lindau syndrome is also caused by VHL variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (147 disease-causing).
- Chuvash polycythemia is also caused by VHL variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (116 disease-causing).
- Pheochromocytoma is also caused by VHL variants; they fall partly in the same places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (4 disease-causing).
- Gastrointestinal stromal tumor is also caused by SDHC variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (16 disease-causing).
- Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHC variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (16 disease-causing).
- Mitochondrial complex II deficiency, nuclear type 1 is also caused by SDHA variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (18 disease-causing).
- Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHA variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (14 disease-causing).
- Neurodegeneration with ataxia and late-onset optic atrophy is also caused by SDHA variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (5 disease-causing).
- Hereditary leiomyomatosis and renal cell cancer is also caused by FH variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (34 disease-causing).
- Fumarase deficiency is also caused by FH variants; they fall mostly in different places as the Inherited phaeochromocytoma and paraganglioma excluding NF1 variants (11 disease-causing).
Diseases related to Inherited phaeochromocytoma and paraganglioma excluding NF1
- Gastrointestinal stromal tumor, also linked to SDHA, SDHB and SDHC
- Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHA, SDHB and SDHC
- Hereditary pheochromocytoma and paraganglioma, also linked to SDHA, SDHB and SDHC
- Pheochromocytoma, also linked to SDHB and VHL
- Carney-Stratakis syndrome, also linked to SDHB and SDHC
- Von Hippel-Lindau syndrome, also linked to VHL
- Chuvash polycythemia, also linked to VHL
- Ovarian cancer, also linked to FH
- Hereditary leiomyomatosis and renal cell cancer, also linked to FH
- Mitochondrial complex II deficiency, nuclear type 1, also linked to SDHA
- Fumarase deficiency, also linked to FH
- Mitochondrial complex 2 deficiency, nuclear type 3, also linked to SDHB
Frequently asked questions
Which genes are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1?
In CATVariant, Inherited phaeochromocytoma and paraganglioma excluding NF1 is linked to 5 analyzed proteins: SDHB (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial), VHL (von Hippel-Lindau disease tumor suppressor), SDHC (Succinate dehydrogenase cytochrome b560 subunit, mitochondrial), SDHA (Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial) and FH (Fumarate hydratase, mitochondrial).
How many genetic variants are linked to Inherited phaeochromocytoma and paraganglioma excluding NF1?
16 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6 are of uncertain significance or have conflicting reports.
Which uncertain variants in Inherited phaeochromocytoma and paraganglioma excluding NF1 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 Inherited phaeochromocytoma and paraganglioma excluding NF1?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 8 disease-causing and 38 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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