Hereditary spastic paraplegia 33

Summary

Hereditary spastic paraplegia 33 (MONDO:0012448) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 33
Mondo ID	MONDO:0012448
MeSH	C565214
OMIM	610244
DOID	DOID:0110784
UMLS	C1853251
MedGen	339943
GARD	0024867
Is cancer (heuristic)	no

Also known as: hereditary spastic paraplegia caused by mutation in ZFYVE27 · hereditary spastic paraplegia type 33 · spastic paraplegia 33, autosomal dominant · SPG33 · ZFYVE27 hereditary spastic paraplegia

Data availability: 78 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › hereditary spastic paraplegia 33

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

78 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 30 benign, 5 benign/likely benign, 5 likely benign, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1289	NM_001385875.1(ZFYVE27):c.572G>T (p.Gly191Val)	ZFYVE27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880086	NM_001385875.1(ZFYVE27):c.805-5C>T	ZFYVE27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880087	NM_001385875.1(ZFYVE27):c.913G>A (p.Ala305Thr)	ZFYVE27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301845	NM_001385875.1(ZFYVE27):c.*223G>C	LOC130004486	Uncertain significance	criteria provided, single submitter
1709552	NM_001385875.1(ZFYVE27):c.1078C>G (p.Leu360Val)	ZFYVE27	Uncertain significance	criteria provided, single submitter
2438650	NM_001385875.1(ZFYVE27):c.815C>T (p.Pro272Leu)	ZFYVE27	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438651	NM_001385875.1(ZFYVE27):c.310G>A (p.Ala104Thr)	ZFYVE27	Uncertain significance	criteria provided, single submitter
301830	NM_001385875.1(ZFYVE27):c.386G>A (p.Ser129Asn)	ZFYVE27	Uncertain significance	criteria provided, multiple submitters, no conflicts
301836	NM_001385875.1(ZFYVE27):c.797C>T (p.Pro266Leu)	ZFYVE27	Uncertain significance	criteria provided, single submitter
301838	NM_001385875.1(ZFYVE27):c.914C>T (p.Ala305Val)	ZFYVE27	Uncertain significance	criteria provided, single submitter
301849	NM_001385875.1(ZFYVE27):c.*678A>C	ZFYVE27	Uncertain significance	criteria provided, single submitter
301853	NM_001385875.1(ZFYVE27):c.*945G>A	ZFYVE27	Uncertain significance	criteria provided, single submitter
301855	NM_001385875.1(ZFYVE27):c.*1148C>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
301857	NM_001385875.1(ZFYVE27):c.*1195C>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
301859	NM_001385875.1(ZFYVE27):c.*1283C>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
301862	NM_001385875.1(ZFYVE27):c.*1340G>C	ZFYVE27	Uncertain significance	criteria provided, single submitter
301865	NM_001385875.1(ZFYVE27):c.*1450G>A	ZFYVE27	Uncertain significance	criteria provided, single submitter
301866	NM_001385875.1(ZFYVE27):c.*1472C>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
4081023	NM_001385875.1(ZFYVE27):c.898-3_924del	ZFYVE27	Uncertain significance	criteria provided, single submitter
851871	NM_001385875.1(ZFYVE27):c.149A>G (p.Tyr50Cys)	ZFYVE27	Uncertain significance	criteria provided, multiple submitters, no conflicts
877229	NM_001385875.1(ZFYVE27):c.-1-10A>G	ZFYVE27	Uncertain significance	criteria provided, single submitter
877287	NM_001385875.1(ZFYVE27):c.*52C>A	ZFYVE27	Uncertain significance	criteria provided, single submitter
877288	NM_001385875.1(ZFYVE27):c.*57C>G	ZFYVE27	Uncertain significance	criteria provided, single submitter
877342	NM_001385875.1(ZFYVE27):c.*1211G>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
877343	NM_001385875.1(ZFYVE27):c.*1308A>G	ZFYVE27	Uncertain significance	criteria provided, single submitter
878267	NM_001385875.1(ZFYVE27):c.197+8C>T	ZFYVE27	Uncertain significance	criteria provided, single submitter
878268	NM_001385875.1(ZFYVE27):c.219C>G (p.Ser73=)	ZFYVE27	Uncertain significance	criteria provided, single submitter
878326	NM_001385875.1(ZFYVE27):c.*211T>G	ZFYVE27	Uncertain significance	criteria provided, single submitter
878364	NM_001385875.1(ZFYVE27):c.*1428A>C	ZFYVE27	Uncertain significance	criteria provided, single submitter
878365	NM_001385875.1(ZFYVE27):c.*1442A>C	ZFYVE27	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
ZFYVE27	Limited	Autosomal dominant	hereditary spastic paraplegia 33	2

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
ZFYVE27	HGNC:26559	ENSG00000155256	Q5T4F4	Protrudin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZFYVE27	Protrudin	Key regulator of RAB11-dependent vesicular trafficking during neurite extension through polarized membrane transport.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZFYVE27	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD

Expression context

Cohort genes with no expression data: 0.

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
ileal mucosa	1
pancreatic ductal cell	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZFYVE27	216	ubiquitous	yes	pancreatic ductal cell, right hemisphere of cerebellum, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZFYVE27	1,282

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZFYVE27	Q5T4F4	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
endoplasmic reticulum tubular network formation	1	2808.7×	0.002	ZFYVE27
neurotrophin TRK receptor signaling pathway	1	1053.2×	0.003	ZFYVE27
positive regulation of axon extension	1	510.7×	0.004	ZFYVE27
neuron projection development	1	122.1×	0.010	ZFYVE27
protein localization to plasma membrane	1	108.7×	0.010	ZFYVE27
vesicle-mediated transport	1	96.3×	0.010	ZFYVE27

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
ZFYVE27	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	ZFYVE27

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)
ZFYVE27	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.