ZFYVE26

Summary

ZFYVE26 (zinc finger FYVE-type containing 26, HGNC:20761) is a protein-coding gene on chromosome 14q24.1, encoding Zinc finger FYVE domain-containing protein 26 (Q68DK2). Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission.

This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15.

Source: NCBI Gene 23503 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 15 (Definitive, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 3,078 total — 198 pathogenic, 197 likely-pathogenic
• Phenotypes (HPO): 56
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_015346

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20761
Approved symbol	ZFYVE26
Name	zinc finger FYVE-type containing 26
Location	14q24.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0321
Ensembl gene	ENSG00000072121
Ensembl biotype	protein_coding
OMIM	612012
Entrez	23503

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay

ENST00000347230, ENST00000394455, ENST00000553399, ENST00000554523, ENST00000554557, ENST00000554783, ENST00000555452, ENST00000557204, ENST00000557306, ENST00000557366, ENST00000557407, ENST00000676512, ENST00000676620, ENST00000677026, ENST00000678382, ENST00000678386

RefSeq mRNA: 1 — MANE Select: NM_015346 NM_015346

CCDS: CCDS9788

Canonical transcript exons

ENST00000347230 — 42 exons

Exon	Start	End
ENSE00001395974	67746522	67748639
ENSE00002432945	67816534	67816590
ENSE00003458773	67806545	67806675
ENSE00003464728	67790572	67790773
ENSE00003468119	67754071	67754212
ENSE00003474408	67794171	67794239
ENSE00003477810	67775860	67776106
ENSE00003486315	67785858	67786022
ENSE00003497427	67755948	67756145
ENSE00003500827	67769594	67769730
ENSE00003501705	67752344	67752526
ENSE00003504681	67753707	67753766
ENSE00003506013	67781333	67781529
ENSE00003517293	67793608	67793759
ENSE00003518903	67775016	67775114
ENSE00003524019	67798014	67798622
ENSE00003535663	67762203	67762412
ENSE00003542727	67751052	67751096
ENSE00003545215	67778126	67778248
ENSE00003546026	67762672	67762819
ENSE00003555322	67815770	67816046
ENSE00003561359	67786114	67786233
ENSE00003564834	67780241	67780345
ENSE00003571647	67784334	67784436
ENSE00003572633	67785059	67785277
ENSE00003588127	67805217	67805305
ENSE00003590759	67813986	67814064
ENSE00003592606	67809200	67809289
ENSE00003603448	67797672	67797755
ENSE00003628771	67766227	67766447
ENSE00003641291	67782780	67783525
ENSE00003641866	67767704	67767840
ENSE00003643956	67768517	67768548
ENSE00003645209	67777559	67777735
ENSE00003645884	67789335	67789598
ENSE00003653557	67772047	67772210
ENSE00003653924	67804101	67804264
ENSE00003663476	67807398	67807920
ENSE00003664392	67802079	67802282
ENSE00003683260	67755051	67755250
ENSE00003685299	67805454	67805618
ENSE00003685807	67761366	67761584

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 91.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.8673 / max 422.5524, expressed in 1804 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143767	16.4938	1804
143763	0.1426	32
143762	0.1242	27
143766	0.0415	12
143764	0.0401	13
143765	0.0162	7
143761	0.0088	3

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	91.46	gold quality
endothelial cell	CL:0000115	88.00	gold quality
visceral pleura	UBERON:0002401	85.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.42	gold quality
cervix squamous epithelium	UBERON:0006922	85.02	silver quality
medial globus pallidus	UBERON:0002477	84.73	gold quality
tendon of biceps brachii	UBERON:0008188	84.48	gold quality
biceps brachii	UBERON:0001507	84.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.83	gold quality
colonic epithelium	UBERON:0000397	83.71	gold quality
stromal cell of endometrium	CL:0002255	83.66	gold quality
pleura	UBERON:0000977	83.39	gold quality
adrenal tissue	UBERON:0018303	83.27	gold quality
germinal epithelium of ovary	UBERON:0001304	83.07	gold quality
ventricular zone	UBERON:0003053	83.07	gold quality
bone marrow cell	CL:0002092	82.89	gold quality
choroid plexus epithelium	UBERON:0003911	82.89	gold quality
trabecular bone tissue	UBERON:0002483	82.84	gold quality
muscle of leg	UBERON:0001383	82.75	gold quality
parietal pleura	UBERON:0002400	82.69	gold quality
gastrocnemius	UBERON:0001388	82.58	gold quality
tendon	UBERON:0000043	82.54	gold quality
bronchial epithelial cell	CL:0002328	82.36	gold quality
globus pallidus	UBERON:0001875	82.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.21	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.20	gold quality
muscle organ	UBERON:0001630	82.04	gold quality
jejunal mucosa	UBERON:0000399	81.84	gold quality
hair follicle	UBERON:0002073	81.45	silver quality
granulocyte	CL:0000094	81.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

175 targeting ZFYVE26, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• phenotypic heterogeneity of SPG15 in which mental retardation or cognitive deterioration, but not all other signs of Kjellin syndrome, are associated with hereditary spastic paraplegia and significantly reduces the SPG15 locus (PMID:17661097)
• Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity. (PMID:18332254)
• Refinement of SPG15 to a 2.64 Mb genetic interval on chromosome 14q23.3-q24.2 and the identification of ZFYVE26 was reported in families with complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. (PMID:18394578)
• Of patients with hereditary spastic paraplegia-thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. (PMID:19805727)
• phenotype and mutation frequency compared with SPG11 in complicated hereditary spastic paraplegia (PMID:19917823)
• PtdIns(3)P production is essential for proper cytokinesis. PtdIns(3)P-binding centrosomal protein FYVE-CENT and TTC19 control cytokinesis through their translocation from the centrosome to the midbody mediated by the kinesin protein KIF13A. (PMID:20208530)
• Findings suggest a positive feedback loop for recruitment of FYVE-CENT and Beclin 1 to the intercellular bridge during cytokinesis, and reveal a novel potential tumor suppressor mechanism for Beclin 1. (PMID:21455500)
• SPG15 was strongly expressed in cortical and spinal motor neurons and in embryos. It partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum, microtubules and the mitochondria surface. (PMID:21545838)
• We propose AP-5, SPG15, SPG11 form a coat-like complex, with AP-5 involved in protein sorting, SPG15 facilitating docking of the coat onto membranes by interacting with PI3P via its FYVE domain, and SPG11 (possibly together with SPG15) forming a scaffold. (PMID:23825025)
• spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. (PMID:24030950)
• ZFYVE26 is a key determinant of autophagosome maturation (PMID:24284334)
• spg15 should be search for in the case of juvenile levodopa reponsive parkinsonism (PMID:24366652)
• spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration. (PMID:25365221)
• Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease (PMID:26492578)
• Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of hereditary spastic paraplegia (HSP) , SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. (PMID:29726929)
• ZFYVE26 and SPG11 are differently involved in autophagy and endocytosis. (PMID:30081747)
• Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia. (PMID:32006740)
• Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia. (PMID:33637369)
• Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families. (PMID:33771085)
• The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15. (PMID:36315648)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zfyve26	ENSDARG00000040131
mus_musculus	Zfyve26	ENSMUSG00000066440
rattus_norvegicus	Zfyve26	ENSRNOG00000059875
drosophila_melanogaster	CG6051	FBGN0039492
drosophila_melanogaster	CG31064	FBGN0051064
caenorhabditis_elegans		WBGENE00003084

Paralogs (13): RUFY3 (ENSG00000018189), ZFYVE16 (ENSG00000039319), SNX29 (ENSG00000048471), RUNDC3B (ENSG00000105784), RUNDC3A (ENSG00000108309), PLEKHM2 (ENSG00000116786), ZFYVE28 (ENSG00000159733), ZFYVE1 (ENSG00000165861), ZFYVE19 (ENSG00000166140), PLEKHF1 (ENSG00000166289), PLEKHF2 (ENSG00000175895), RUFY1 (ENSG00000176783), RUFY2 (ENSG00000204130)

Protein

Protein identifiers

Zinc finger FYVE domain-containing protein 26 — Q68DK2 (reviewed: Q68DK2)

Alternative names: FYVE domain-containing centrosomal protein, Spastizin

All UniProt accessions (9): Q68DK2, A0A2H2FF08, A0A7I2V403, A0A7I2V4E6, A0A7I2V577, A0A7I2YQU3, A0A7I2YQV0, G3V230, G3V2D8

UniProt curated annotations — full annotation on UniProt →

Function. Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission. May also be required for efficient homologous recombination DNA double-strand break repair.

Subunit / interactions. Interacts with AP5Z1, AP5B1, AP5S1 and SPG11. Interacts with TTC19 and KIF13A.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Midbody.

Tissue specificity. Strongest expression in the adrenal gland, bone marrow, adult brain, fetal brain, lung, placenta, prostate, skeletal muscle, testis, thymus, and retina. Intermediate levels are detected in other structures, including the spinal cord.

Disease relevance. Spastic paraplegia 15, autosomal recessive (SPG15) [MIM:270700] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG15 is a complex form associated with additional neurological symptoms such as cognitive deterioration or intellectual disability, axonal neuropathy, mild cerebellar signs, and, less frequently, a central hearing deficit, decreased visual acuity, or retinal degeneration. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FYVE-type zinc finger mediates binding to phosphatidylinositol 3-phosphate and recruitment to the midbody during cytokinesis.

Isoforms (5)

UniProt ID	Names	Canonical?
Q68DK2-1	1	yes
Q68DK2-2	2
Q68DK2-4	4
Q68DK2-3	3
Q68DK2-5	5

RefSeq proteins (1): NP_056161* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR028730	ZFYVE26	Family
IPR057946	TPR_ZFYVE26	Domain

Pfam: PF01363, PF25569

UniProt features (67 total): sequence conflict 18, sequence variant 11, modified residue 9, binding site 8, splice variant 8, region of interest 5, compositionally biased region 4, chain 1, zinc finger region 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8YAD	ELECTRON MICROSCOPY	4.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68DK2-F1	65.71	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 1818; 1821; 1835; 1838; 1843; 1846; 1864; 1867

Post-translational modifications (9): 297, 615, 619, 703, 800, 1742, 1764, 1780, 1782

Mutagenesis-validated functional residues (1):

Position	Phenotype
1836	abolishes phosphatidylinositol 3-phosphate-binding and localization to the midbody.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 358 (showing top): GOBP_MITOTIC_CYTOKINESIS, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, CAGCTG_AP4_Q5, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_MACROAUTOPHAGY, chr14q24, GOBP_CYTOKINESIS, GOBP_REGULATION_OF_CELL_CYCLE, USF_01, GOCC_CENTROSOME, GOBP_REGULATION_OF_CYTOKINESIS, GOBP_REGULATION_OF_CELL_DIVISION, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (8): mitotic cytokinesis (GO:0000281), double-strand break repair via homologous recombination (GO:0000724), lysosome organization (GO:0007040), regulation of cytokinesis (GO:0032465), autophagosome organization (GO:1905037), DNA repair (GO:0006281), DNA damage response (GO:0006974), cell division (GO:0051301)

GO Molecular Function (6): zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), phosphatidylinositol-3-phosphate binding (GO:0032266), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (8): lysosome (GO:0005764), lysosomal membrane (GO:0005765), early endosome (GO:0005769), late endosome (GO:0005770), centrosome (GO:0005813), midbody (GO:0030496), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
endosome	2
cellular anatomical structure	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
recombinational repair	1
double-strand break repair	1
lytic vacuole organization	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
vacuole organization	1
macroautophagy	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
cellular process	1
transition metal ion binding	1
kinase binding	1
phosphatidylinositol phosphate binding	1
cation binding	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
centriole	1
microtubule organizing center	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZFYVE26	AP5Z1	O43299	992
ZFYVE26	SPG11	Q96JI7	983
ZFYVE26	AP5S1	Q9NUS5	939
ZFYVE26	AP5B1	Q2VPB7	905
ZFYVE26	TTC19	Q6DKK2	866
ZFYVE26	SPAST	Q9UBP0	784
ZFYVE26	BECN1	Q14457	716
ZFYVE26	ATL1	Q8WXF7	703
ZFYVE26	SPG21	Q9NZD8	694
ZFYVE26	SPG7	Q9UQ90	665
ZFYVE26	TECPR2	O15040	663
ZFYVE26	WASHC5	Q12768	654
ZFYVE26	REEP1	Q9H902	649
ZFYVE26	SPART	Q8N0X7	629
ZFYVE26	NIPA1	Q7RTP0	618

IntAct

61 interactions, top by confidence:

A	B	Type	Score
RUBCN	BECN1	psi-mi:“MI:0914”(association)	0.920
ZFYVE26	SPG11	psi-mi:“MI:2364”(proximity)	0.700
SPG11	ZFYVE26	psi-mi:“MI:0915”(physical association)	0.700
ZFYVE26	SPG11	psi-mi:“MI:0915”(physical association)	0.700
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
ZFYVE26	AP5Z1	psi-mi:“MI:0914”(association)	0.540
ZFYVE26	AP5Z1	psi-mi:“MI:0915”(physical association)	0.540
AP5Z1	ZFYVE26	psi-mi:“MI:0403”(colocalization)	0.540
AP5Z1	ZFYVE26	psi-mi:“MI:0915”(physical association)	0.540
AP5S1	AP5Z1	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
ZFYVE26	ZFYVE26	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (60): ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), ZFYVE26 (Two-hybrid), TFIP11 (Two-hybrid), CEP44 (Two-hybrid), USHBP1 (Two-hybrid), PNMA5 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-7 (Two-hybrid)

ESM2 similar proteins: A0A096P2H6, A0A0D9S1R4, A0A2Y9GDB5, A0JNN2, A8MXV6, D2H5P6, E1BLZ4, E1C7U0, P0DKW1, P0DKW2, P0DKW3, P0DKW4, P0DKY3, P0DML4, P0DML5, P0DML6, P0DMN8, P0DOC4, P0DP53, P0DTG9, P0DTH0, P0DTH1, P0DTH2, P0DTH3, P0DTH4, P0DUP6, P24001, P55056, P55797, Q2TBQ4, Q32KP7, Q3SYR5, Q5EAA5, Q5JX69, Q5R7E2, Q5U2R2, Q68DK2, Q6MG51, Q6P0A1, Q6UJB9

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PIP3	“up-regulates quantity”	ZFYVE26	relocalization
ZFYVE26	“up-regulates activity”	TTC19	binding
KIF13A	“up-regulates activity”	ZFYVE26	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

3078 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	198
Likely pathogenic	197
Uncertain significance	895
Likely benign	1481
Benign	115

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027980	NM_015346.4(ZFYVE26):c.886+1G>C	Pathogenic
1031907	NM_015346.4(ZFYVE26):c.1564C>T (p.Gln522Ter)	Pathogenic
1068462	NM_015346.4(ZFYVE26):c.2620C>T (p.Gln874Ter)	Pathogenic
1068663	NM_015346.4(ZFYVE26):c.2271C>G (p.Tyr757Ter)	Pathogenic
1068674	NM_015346.4(ZFYVE26):c.5355_5376dup (p.Pro1793fs)	Pathogenic
1068816	NM_015346.4(ZFYVE26):c.5028dup (p.Asn1677Ter)	Pathogenic
1069531	NM_015346.4(ZFYVE26):c.4182G>A (p.Trp1394Ter)	Pathogenic
1070388	NC_000014.8:g.(?68251041)(68282690_?)del	Pathogenic
1070442	NM_015346.4(ZFYVE26):c.2675C>G (p.Ser892Ter)	Pathogenic
1070842	NM_015346.4(ZFYVE26):c.308del (p.Glu103fs)	Pathogenic
1070930	NM_015346.4(ZFYVE26):c.6011+1del	Pathogenic
1071346	NM_015346.4(ZFYVE26):c.6775C>T (p.Gln2259Ter)	Pathogenic
1072208	NM_015346.4(ZFYVE26):c.5857C>T (p.Gln1953Ter)	Pathogenic
1072638	NM_015346.4(ZFYVE26):c.5254del (p.Gln1752fs)	Pathogenic
1073452	NM_015346.4(ZFYVE26):c.2795del (p.Leu932fs)	Pathogenic
1073502	NM_015346.4(ZFYVE26):c.6757del (p.Ile2253fs)	Pathogenic
1073753	NM_015346.4(ZFYVE26):c.6480C>G (p.Tyr2160Ter)	Pathogenic
1073888	NM_015346.4(ZFYVE26):c.4599G>A (p.Trp1533Ter)	Pathogenic
1074144	NM_015346.4(ZFYVE26):c.2114dup (p.Pro705_Glu706insTer)	Pathogenic
1074402	NM_015346.4(ZFYVE26):c.4144C>T (p.Gln1382Ter)	Pathogenic
1074761	NM_015346.4(ZFYVE26):c.2504C>G (p.Ser835Ter)	Pathogenic
1075472	NM_015346.4(ZFYVE26):c.5111del (p.Leu1704fs)	Pathogenic
1076109	NM_015346.4(ZFYVE26):c.7195del (p.Gln2399fs)	Pathogenic
1076370	NM_015346.4(ZFYVE26):c.3182del (p.Ile1061fs)	Pathogenic
1076426	NM_015346.4(ZFYVE26):c.6360del (p.Phe2120fs)	Pathogenic
1323783	NM_015346.4(ZFYVE26):c.5428dup (p.Val1810fs)	Pathogenic
1344188	NM_015346.4(ZFYVE26):c.2609_2633del (p.Met870fs)	Pathogenic
1363992	NM_015346.4(ZFYVE26):c.3253C>T (p.Gln1085Ter)	Pathogenic
1365553	NM_015346.4(ZFYVE26):c.6112del (p.Arg2037_Leu2038insTer)	Pathogenic
1366870	NC_000014.8:g.(?68256042)(68282690_?)del	Pathogenic

SpliceAI

6018 predictions. Top by Δscore:

Variant	Effect	Δscore
14:67729186:CCCA:C	acceptor_loss	1.0000
14:67729187:CCAG:C	acceptor_loss	1.0000
14:67729188:CA:C	acceptor_loss	1.0000
14:67729189:A:AG	acceptor_gain	1.0000
14:67729190:G:GG	acceptor_gain	1.0000
14:67729190:G:GT	acceptor_loss	1.0000
14:67729366:TGGC:T	donor_gain	1.0000
14:67752338:GTGTA:G	donor_loss	1.0000
14:67752340:GTACC:G	donor_loss	1.0000
14:67752341:TA:T	donor_loss	1.0000
14:67752342:A:C	donor_loss	1.0000
14:67752343:C:G	donor_loss	1.0000
14:67752369:T:TA	donor_gain	1.0000
14:67752522:AAGTC:A	acceptor_gain	1.0000
14:67752523:AGTC:A	acceptor_gain	1.0000
14:67752524:GTC:G	acceptor_gain	1.0000
14:67752525:TC:T	acceptor_gain	1.0000
14:67752526:CC:C	acceptor_gain	1.0000
14:67752527:C:CC	acceptor_gain	1.0000
14:67752527:C:T	acceptor_gain	1.0000
14:67752533:C:CT	acceptor_gain	1.0000
14:67752534:A:T	acceptor_gain	1.0000
14:67755048:TA:T	donor_loss	1.0000
14:67755049:ACC:A	donor_loss	1.0000
14:67755050:CCTT:C	donor_loss	1.0000
14:67755052:TTGAC:T	donor_gain	1.0000
14:67755100:T:TA	donor_gain	1.0000
14:67755246:TGGTC:T	acceptor_gain	1.0000
14:67755247:GGTC:G	acceptor_gain	1.0000
14:67755248:GTC:G	acceptor_gain	1.0000

AlphaMissense

16562 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:67755141:A:G	L2299P	0.999
14:67769710:A:C	C1835W	0.999
14:67769712:A:G	C1835R	0.999
14:67772077:G:C	C1818W	0.999
14:67772079:A:G	C1818R	0.999
14:67772104:C:A	W1809C	0.999
14:67772104:C:G	W1809C	0.999
14:67752441:A:G	L2425P	0.998
14:67753731:A:C	F2388L	0.998
14:67753731:A:T	F2388L	0.998
14:67753733:A:G	F2388L	0.998
14:67754192:A:G	L2336P	0.998
14:67755234:G:T	A2268D	0.998
14:67755235:C:G	A2268P	0.998
14:67755249:T:G	D2263A	0.998
14:67755250:C:G	D2263H	0.998
14:67755964:A:G	L2257P	0.998
14:67762351:A:G	L2074P	0.998
14:67762706:A:G	L2042P	0.998
14:67769688:A:G	C1843R	0.998
14:67769696:C:G	R1840P	0.998
14:67769699:C:T	G1839D	0.998
14:67769703:A:G	C1838R	0.998
14:67769711:C:G	C1835S	0.998
14:67769711:C:T	C1835Y	0.998
14:67769712:A:T	C1835S	0.998
14:67769715:G:C	H1834D	0.998
14:67772078:C:T	C1818Y	0.998
14:67772106:A:G	W1809R	0.998
14:67772106:A:T	W1809R	0.998

dbSNP variants (sampled 300 via entrez): RS1000057308 (14:67763630 C>T), RS1000097034 (14:67764011 C>A), RS1000117773 (14:67757101 A>G), RS1000153210 (14:67764455 G>A), RS1000161814 (14:67808567 A>C), RS1000250254 (14:67814054 C>T), RS1000269891 (14:67796374 T>C), RS1000278885 (14:67770237 G>A), RS1000433713 (14:67776477 C>T), RS1000476598 (14:67744883 T>G), RS1000482086 (14:67787956 C>T), RS1000504771 (14:67758564 T>C), RS1000511956 (14:67763961 C>T), RS1000560493 (14:67768856 A>G), RS1000609211 (14:67794737 G>A)

Disease associations

OMIM: gene MIM:612012 | disease phenotypes: MIM:612712, MIM:270700, MIM:303350, MIM:268000, MIM:204000, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 15	Definitive	Autosomal recessive

Mondo (9): Leber congenital amaurosis 13 (MONDO:0012990), hereditary spastic paraplegia 15 (MONDO:0010044), hereditary spastic paraplegia (MONDO:0019064), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), retinitis pigmentosa 53 (MONDO:0800348), Leber congenital amaurosis (MONDO:0018998), congenital myopathy (MONDO:0019952), intellectual disability (MONDO:0001071)

Orphanet (7): Kjellin syndrome (Orphanet:100996), Hereditary spastic paraplegia (Orphanet:685), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Leber congenital amaurosis (Orphanet:65), Congenital myopathy (Orphanet:97245), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000496	Abnormality of eye movement
HP:0000505	Visual impairment
HP:0000546	Retinal degeneration
HP:0000580	Pigmentary retinopathy
HP:0000608	Macular degeneration
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000726	Dementia
HP:0000819	Diabetes mellitus
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001288	Gait disturbance
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001328	Specific learning disability
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002337_36	Amyotrophic lateral sclerosis (sporadic)	6.000000e-07
GCST007995_43	Asthma (childhood onset)	1.000000e-08
GCST009798_33	Asthma	7.000000e-13

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C567197	Leber Congenital Amaurosis 13 (supp.)
C536642	Spastic paraplegia 15, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
nickel sulfate	decreases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acrolein	increases abundance, affects cotreatment, decreases expression, increases oxidation	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
coumarin	increases phosphorylation	1
resorcinol	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Temozolomide	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	decreases expression	1
Doxorubicin	decreases expression	1
Oxazolone	decreases expression	1
Plant Oils	decreases expression	1

Clinical trials (associated diseases)

291 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)