Pheochromocytoma/paraganglioma syndrome 5

Summary

Pheochromocytoma/paraganglioma syndrome 5 (MONDO:0013602) is a disease caused by SDHA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SDHA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 2,737

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pheochromocytoma/paraganglioma syndrome 5
Mondo ID	MONDO:0013602
OMIM	614165
DOID	DOID:0061220
UMLS	C3279992
MedGen	481622
GARD	0015763
Is cancer (heuristic)	no

Also known as: paraganglioma caused by mutation in SDHA · paragangliomas 5 · paragangliomas type 5 · PGL5 · pheochromocytoma/paraganglioma syndrome 5 · SDHA paraganglioma

Data availability: 2,737 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › autonomic nervous system disorder › autonomic nervous system neoplasm › paraganglioma › pheochromocytoma/paraganglioma syndrome 5

Related subtypes (11): head and neck paraganglioma, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma/paraganglioma syndrome 2, pheochromocytoma/paraganglioma syndrome 3, sporadic pheochromocytoma/secreting paraganglioma, non-secreting paraganglioma, parasympathetic paraganglioma, sympathetic paraganglioma, pheochromocytoma/paraganglioma syndrome 6, pheochromocytoma/paraganglioma syndrome 7

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

600 retrieved; paginated sample, class counts are floors:

275 uncertain significance, 175 likely benign, 68 benign/likely benign, 34 conflicting classifications of pathogenicity, 21 pathogenic, 13 benign, 7 pathogenic/likely pathogenic, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066704	NM_004168.4(SDHA):c.778G>C (p.Gly260Arg)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067845	NM_004168.4(SDHA):c.457-2A>G	SDHA	Pathogenic	criteria provided, single submitter
1069259	NM_004168.4(SDHA):c.1032_1033del (p.Arg345fs)	SDHA	Pathogenic	criteria provided, single submitter
1069906	NM_004168.4(SDHA):c.242_243insA (p.Ser81_Glu82insTer)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070947	NM_004168.4(SDHA):c.1012del (p.Ala338fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1071454	NM_004168.4(SDHA):c.454G>T (p.Glu152Ter)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071644	NM_004168.4(SDHA):c.554dup (p.Ala186fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072916	NM_004168.4(SDHA):c.79C>T (p.Gln27Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1075636	NM_004168.4(SDHA):c.124_125dup (p.Ala43fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1354535	NM_004168.4(SDHA):c.392_396dup (p.Leu133fs)	SDHA	Pathogenic	criteria provided, single submitter
1357420	NM_004168.4(SDHA):c.1245dup (p.Asn416fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1370664	NM_004168.4(SDHA):c.467dup (p.Tyr156Ter)	SDHA	Pathogenic	criteria provided, single submitter
1389565	NM_004168.4(SDHA):c.1764dup (p.Arg589fs)	SDHA	Pathogenic	criteria provided, single submitter
1401495	NM_004168.4(SDHA):c.1035del (p.Ser346fs)	SDHA	Pathogenic	criteria provided, single submitter
1405170	NM_004168.4(SDHA):c.1755_1759del (p.Lys586fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1408872	NM_004168.4(SDHA):c.3G>T (p.Met1Ile)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
141876	NM_004168.4(SDHA):c.667del (p.Asp223fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425164	NM_004168.4(SDHA):c.1558C>T (p.Gln520Ter)	SDHA	Pathogenic	criteria provided, single submitter
1436702	NM_004168.4(SDHA):c.322_323del (p.Asn108fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442909	NM_004168.4(SDHA):c.1470_1473dup (p.Ser492fs)	SDHA	Pathogenic	criteria provided, single submitter
1451165	NM_004168.4(SDHA):c.23C>A (p.Ser8Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1453363	NM_004168.4(SDHA):c.633T>G (p.Tyr211Ter)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1453517	NM_004168.4(SDHA):c.1743_1744del (p.Ala582fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1455102	NM_004168.4(SDHA):c.3G>C (p.Met1Ile)	SDHA	Pathogenic	criteria provided, single submitter
1455577	NM_004168.4(SDHA):c.298_299del (p.Thr100fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456663	NM_004168.4(SDHA):c.65G>A (p.Trp22Ter)	SDHA	Pathogenic	criteria provided, single submitter
1458523	NM_004168.4(SDHA):c.1658_1661del (p.Asp553fs)	SDHA	Pathogenic	criteria provided, single submitter
1458794	NM_004168.4(SDHA):c.447del (p.Val150fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
1067316	NM_004168.4(SDHA):c.771-1G>C	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068401	NM_004168.4(SDHA):c.1664-2A>G	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 8 · 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
SDHA	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
ZMYND11	Orphanet:687424	ZMYND11-related developmental delay-speech delay-seizures-behavioral abnormalities-craniofacial dysmorphism syndrome due to 10p15.3 microdeletion
ZMYND11	Orphanet:694308	ZMYND11-related developmental delay-speech delay-seizures-behavioral abnormalities-craniofacial dysmorphism syndrome due to a point mutation

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	gencc,clinvar
ZMYND11	HGNC:16966	ENSG00000015171	Q15326	Zinc finger MYND domain-containing protein 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
ZMYND11	Zinc finger MYND domain-containing protein 11	Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at ‘Lys-36’ (H3.3K36me3) and regulates RNA polymerase II elongation.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
ZMYND11	Transcription factor	no		PWWP_dom, Bromodomain, Znf_PHD

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1
caput epididymis	1
cauda epididymis	1
cranial nerve II	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
ZMYND11	301	ubiquitous	marker	cranial nerve II, caput epididymis, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
ZMYND11	1,264

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZMYND11	Q15326	8
SDHA	P31040	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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×	0.006	SDHA
Citric acid cycle (TCA cycle)	1	423.0×	0.006	SDHA
Respiratory electron transport	1	95.2×	0.014	SDHA
Aerobic respiration and respiratory electron transport	1	88.5×	0.014	SDHA
Metabolism	1	11.6×	0.086	SDHA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
succinate metabolic process	1	1685.2×	0.004	SDHA
mitochondrial electron transport, succinate to ubiquinone	1	1685.2×	0.004	SDHA
respiratory electron transport chain	1	421.3×	0.008	SDHA
regulation of transcription elongation by RNA polymerase II	1	401.2×	0.008	ZMYND11
negative regulation of JNK cascade	1	280.9×	0.008	ZMYND11
tricarboxylic acid cycle	1	255.3×	0.008	SDHA
negative regulation of extrinsic apoptotic signaling pathway	1	210.7×	0.009	ZMYND11
regulation of signal transduction	1	133.8×	0.011	ZMYND11
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.011	SDHA
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.015	ZMYND11
defense response to virus	1	34.7×	0.034	ZMYND11
nervous system development	1	23.0×	0.047	SDHA
negative regulation of DNA-templated transcription	1	15.8×	0.062	ZMYND11

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHA	1	4
ZMYND11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SDHA	3	Binding:3
ZMYND11	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
LINEZOLID	4	SDHA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SDHA
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	ZMYND11

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)
ZMYND11	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.