Pheochromocytoma/paraganglioma syndrome 2

Summary

Pheochromocytoma/paraganglioma syndrome 2 (MONDO:0011121) is a disease caused by SDHAF2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SDHAF2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 64

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pheochromocytoma/paraganglioma syndrome 2
Mondo ID	MONDO:0011121
MeSH	C566646
OMIM	601650
DOID	DOID:0061217
UMLS	C1866552
MedGen	357076
GARD	0010544
Is cancer (heuristic)	no

Also known as: paraganglioma caused by mutation in SDHAF2 · paragangliomas 2 · paragangliomas type 2 · PGL2 · pheochromocytoma/paraganglioma syndrome 2 · SDHAF2 paraganglioma · SDHAF2-related hereditary paraganglioma-pheochromocytoma syndrome (paragangliomas 2) · SDHAF2-related tumor predisposition

Data availability: 64 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › pheochromocytoma/paraganglioma syndrome 2

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

64 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 15 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign/likely benign, 1 not provided, 1 benign, 1 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451128	NM_017841.4(SDHAF2):c.267del (p.Phe89fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452374	NM_017841.4(SDHAF2):c.229_230del (p.Arg77fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1794666	NM_017841.4(SDHAF2):c.267dup (p.Ala90fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
401	NM_017841.4(SDHAF2):c.232G>A (p.Gly78Arg)	SDHAF2	Pathogenic	criteria provided, multiple submitters, no conflicts
532508	NM_017841.4(SDHAF2):c.305_306insA (p.Asn103fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
806678	NM_017841.4(SDHAF2):c.37-1G>C	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
823022	NM_017841.4(SDHAF2):c.315T>A (p.Tyr105Ter)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678639	NM_017841.4(SDHAF2):c.301C>T (p.Gln101Ter)	SDHAF2	Likely pathogenic	criteria provided, single submitter
3240438	NM_017841.4(SDHAF2):c.406del (p.Val136fs)	SDHAF2	Likely pathogenic	criteria provided, single submitter
982784	NM_017841.4(SDHAF2):c.42_45del (p.Ala15fs)	SDHAF2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
241218	NM_017841.4(SDHAF2):c.490A>G (p.Lys164Glu)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
403423	NM_017841.4(SDHAF2):c.355dup (p.Tyr119fs)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411604	NM_017841.4(SDHAF2):c.371-2A>G	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411605	NM_017841.4(SDHAF2):c.476A>C (p.Glu159Ala)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411607	NM_017841.4(SDHAF2):c.7G>T (p.Val3Leu)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411611	NM_017841.4(SDHAF2):c.331G>A (p.Glu111Lys)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41836	NM_017841.4(SDHAF2):c.52A>G (p.Arg18Gly)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463820	NM_017841.4(SDHAF2):c.25A>G (p.Thr9Ala)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463824	NM_017841.4(SDHAF2):c.320G>A (p.Arg107His)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463831	NM_017841.4(SDHAF2):c.497G>A (p.Arg166His)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486408	NM_017841.4(SDHAF2):c.260+3A>G	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
575138	NM_017841.4(SDHAF2):c.341A>G (p.Asn114Ser)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576139	NM_017841.4(SDHAF2):c.194C>T (p.Thr65Ile)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
647376	NM_017841.4(SDHAF2):c.11C>G (p.Ser4Cys)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
951169	NM_017841.4(SDHAF2):c.96A>T (p.Arg32Ser)	SDHAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045367	NM_017841.4(SDHAF2):c.370+3A>G	SDHAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1056998	NM_017841.4(SDHAF2):c.451C>G (p.Gln151Glu)	SDHAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348817	NM_017841.4(SDHAF2):c.437A>G (p.Asn146Ser)	SDHAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1375076	NM_017841.4(SDHAF2):c.382G>C (p.Ala128Pro)	SDHAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1392150	NM_017841.4(SDHAF2):c.32C>G (p.Ser11Trp)	SDHAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SDHAF2	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHAF2	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHAF2	HGNC:26034	ENSG00000167985	Q9NX18	Succinate dehydrogenase assembly factor 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHAF2	Succinate dehydrogenase assembly factor 2, mitochondrial	Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transpor…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHAF2	Other/Unknown	no		SDH, SDHAF2, SDH_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
granulocyte	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHAF2	229	ubiquitous	marker	islet of Langerhans, adenohypophysis, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHAF2	1,417

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SDHAF2	Q9NX18	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.005	SDHAF2
Citric acid cycle (TCA cycle)	1	423.0×	0.005	SDHAF2
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SDHAF2
Metabolism	1	11.6×	0.086	SDHAF2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein-FAD linkage	1	16852.0×	4e-04	SDHAF2
mitochondrial respiratory chain complex II assembly	1	4213.0×	7e-04	SDHAF2
mitochondrial electron transport, succinate to ubiquinone	1	3370.4×	7e-04	SDHAF2
tricarboxylic acid cycle	1	510.7×	0.003	SDHAF2
negative regulation of epithelial to mesenchymal transition	1	411.0×	0.003	SDHAF2
protein dephosphorylation	1	221.7×	0.005	SDHAF2
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.008	SDHAF2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHAF2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SDHAF2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHAF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.