PGAP1

Summary

PGAP1 (post-GPI attachment to proteins inositol deacylase 1, HGNC:25712) is a protein-coding gene on chromosome 2q33.1, encoding GPI inositol-deacylase (Q75T13). GPI inositol-deacylase that catalyzes the remove of the acyl chain linked to the 2-OH position of inositol ring from the GPI-anchored protein (GPI-AP) in the endoplasmic reticulum.

The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment.

Source: NCBI Gene 80055 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 42 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 569 total — 26 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 70
• MANE Select transcript: NM_024989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25712
Approved symbol	PGAP1
Name	post-GPI attachment to proteins inositol deacylase 1
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12377, Bst1, SPG67
Ensembl gene	ENSG00000197121
Ensembl biotype	protein_coding
OMIM	611655
Entrez	80055

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000354764, ENST00000374738, ENST00000409188, ENST00000409475, ENST00000422444, ENST00000423035, ENST00000459896, ENST00000470179, ENST00000476250, ENST00000482051, ENST00000485830, ENST00000862441, ENST00000911521, ENST00000961224

RefSeq mRNA: 3 — MANE Select: NM_024989 NM_001321099, NM_001321100, NM_024989

CCDS: CCDS2318

Canonical transcript exons

ENST00000354764 — 27 exons

Exon	Start	End
ENSE00001731807	196833004	196841372
ENSE00001901317	196926470	196926707
ENSE00003459913	196873685	196873758
ENSE00003465591	196890828	196890911
ENSE00003465618	196873528	196873579
ENSE00003465764	196842721	196842825
ENSE00003473093	196898317	196898369
ENSE00003482341	196897131	196897197
ENSE00003499220	196893140	196893245
ENSE00003507624	196847003	196847200
ENSE00003533540	196875746	196875821
ENSE00003567334	196864987	196865080
ENSE00003573162	196919997	196920150
ENSE00003586050	196916418	196916593
ENSE00003586290	196902585	196902742
ENSE00003609055	196892346	196892401
ENSE00003639779	196847947	196848037
ENSE00003641495	196845882	196846017
ENSE00003647685	196880076	196880153
ENSE00003651016	196870941	196870979
ENSE00003653109	196872960	196873026
ENSE00003663939	196844524	196844574
ENSE00003667201	196912882	196913053
ENSE00003669347	196872441	196872549
ENSE00003680418	196885834	196885880
ENSE00003684429	196843888	196844075
ENSE00003686104	196885424	196885475

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 96.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0383 / max 218.9593, expressed in 1498 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33050	3.5767	1227
33049	1.3854	594
33048	0.9352	481
33054	0.5774	292
33052	0.4391	166
33053	0.0943	39
33051	0.0302	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.80	gold quality
ganglionic eminence	UBERON:0004023	95.16	gold quality
upper leg skin	UBERON:0004262	92.07	gold quality
ventricular zone	UBERON:0003053	91.23	gold quality
embryo	UBERON:0000922	90.35	gold quality
cortical plate	UBERON:0005343	90.35	gold quality
buccal mucosa cell	CL:0002336	88.80	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.24	gold quality
sural nerve	UBERON:0015488	86.20	gold quality
skin of hip	UBERON:0001554	85.76	gold quality
sperm	CL:0000019	85.14	gold quality
choroid plexus epithelium	UBERON:0003911	84.18	gold quality
tibia	UBERON:0000979	84.03	gold quality
visceral pleura	UBERON:0002401	83.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.48	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.25	gold quality
nipple	UBERON:0002030	83.22	gold quality
CA1 field of hippocampus	UBERON:0003881	82.84	gold quality
adenohypophysis	UBERON:0002196	82.60	gold quality
colonic epithelium	UBERON:0000397	82.52	gold quality
medial globus pallidus	UBERON:0002477	82.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.51	gold quality
cerebellar vermis	UBERON:0004720	82.45	gold quality
entorhinal cortex	UBERON:0002728	82.44	gold quality
middle temporal gyrus	UBERON:0002771	82.38	gold quality
male germ cell	CL:0000015	82.17	gold quality
cauda epididymis	UBERON:0004360	82.15	gold quality
pleura	UBERON:0000977	82.12	gold quality
germinal epithelium of ovary	UBERON:0001304	82.02	gold quality
pituitary gland	UBERON:0000007	81.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	25.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

318 targeting PGAP1, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
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-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996

Literature-anchored findings (GeneRIF, showing 7)

• PGAP1 encoded an ER-associated, 922-amino acid membrane protein bearing a lipase consensus motif. (PMID:14734546)
• results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development (PMID:24784135)
• PGAP1 mutation and a proven functional loss of PGAP1 were found in a patient with cerebral visual impairment and intellectual diasability. (PMID:25804403)
• Study confirms homozygous loss-of function mutations in PGAP1 as a cause of severe encephalopathy. (PMID:26050939)
• LncRNA LEMD1-AS1 relieves chondrocyte inflammation by targeting miR-944/PGAP1 in osteoarthritis. (PMID:35686740)
• Downregulation of lncRNA NEAT1 interacts with miR-374b-5p/PGAP1 axis to aggravate the development of osteoarthritis. (PMID:37691099)
• Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis. (PMID:38167496)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgap1	ENSDARG00000062465
mus_musculus	Pgap1	ENSMUSG00000073678
rattus_norvegicus	Pgap1	ENSRNOG00000013388
drosophila_melanogaster	PGAP1	FBGN0029789
caenorhabditis_elegans		WBGENE00011835

Paralogs (1): C2orf66 (ENSG00000187944)

Protein

Protein identifiers

GPI inositol-deacylase — Q75T13 (reviewed: Q75T13)

Alternative names: Post-GPI attachment to proteins factor 1

All UniProt accessions (5): A6NI33, B4DYY6, F8WD75, Q75T13, H7BZN8

UniProt curated annotations — full annotation on UniProt →

Function. GPI inositol-deacylase that catalyzes the remove of the acyl chain linked to the 2-OH position of inositol ring from the GPI-anchored protein (GPI-AP) in the endoplasmic reticulum. Initiates the post-attachment remodeling phase of GPI-AP biogenesis and participates in endoplasmic reticulum (ER)-to-Golgi transport of GPI-anchored protein.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities (NEDDSBA) [MIM:615802] An autosomal recessive disorder characterized by severely delayed global development, with hypotonia, impaired intellectual development, and poor or absent speech. Most patients have spasticity with limb hypertonia and brisk tendon reflexes. Additional features include non-specific dysmorphic facial features, structural brain abnormalities, and cortical visual impairment. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the GPI inositol-deacylase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q75T13-1	1	yes
Q75T13-2	2
Q75T13-3	3
Q75T13-4	4

RefSeq proteins (3): NP_001308028, NP_001308029, NP_079265* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012908	PGAP1-ab_dom-like	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR039529	PGAP1/BST1	Family
IPR056824	PGAP1_TMD	Domain

Pfam: PF07819, PF24660, PF25140, PF25141

Catalyzed reactions (Rhea), 2 shown:

• [protein]-C-terminal carboxyl phosphoethanolamide-GPI(H8) + H2O = [protein]-C-terminal carboxyl phosphoethanolamide-GPI(deacylinositol-H8) + a fatty acid + H(+) (RHEA:83663)
• [protein]-C-terminal carboxyl phosphoethanolamide-GPI(H7) + H2O = [protein]-C-terminal carboxyl phosphoethanolamide-GPI(deacylinositol-H7) + a fatty acid + H(+) (RHEA:83787)

UniProt features (31 total): topological domain 8, transmembrane region 7, splice variant 5, sequence conflict 4, glycosylation site 2, chain 1, region of interest 1, compositionally biased region 1, active site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q75T13-F1	89.15	0.73

Functional residue map

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

Catalytic / active sites (1): 174

Glycosylation sites (2): 402, 558

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-162791	Attachment of GPI anchor to uPAR

MSigDB gene sets: 696 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_AXIS_SPECIFICATION, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE

GO Biological Process (9): GPI anchor biosynthetic process (GO:0006506), sensory perception of sound (GO:0007605), embryonic pattern specification (GO:0009880), anterior/posterior axis specification (GO:0009948), protein transport (GO:0015031), attachment of GPI anchor to protein (GO:0016255), forebrain regionalization (GO:0021871), positive regulation of ER to Golgi vesicle-mediated transport (GO:1902953), head development (GO:0060322)

GO Molecular Function (4): hydrolase activity, acting on ester bonds (GO:0016788), phosphatidylinositol deacylase activity (GO:0050185), deacylase activity (GO:0160215), hydrolase activity (GO:0016787)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational modification: synthesis of GPI-anchored proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GPI anchored protein biosynthesis	2
catalytic activity	2
cellular anatomical structure	2
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
sensory perception of mechanical stimulus	1
pattern specification process	1
embryo development	1
axis specification	1
anterior/posterior pattern specification	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein maturation	1
regionalization	1
forebrain development	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
positive regulation of intracellular transport	1
regulation of ER to Golgi vesicle-mediated transport	1
anatomical structure development	1
hydrolase activity	1
carboxylic ester hydrolase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGAP1	CD55	P08174	817
PGAP1	PGAP3	Q96FM1	791
PGAP1	PIGK	Q92643	759
PGAP1	PGAP2	Q9UHJ9	753
PGAP1	PIGW	Q7Z7B1	725
PGAP1	PIGT	Q969N2	722
PGAP1	PIGM	Q9H3S5	678
PGAP1	PIGC	Q92535	663
PGAP1	PIGA	P37287	653
PGAP1	PIGB	Q92521	647
PGAP1	GPAA1	O43292	646
PGAP1	PIGL	Q9Y2B2	642
PGAP1	PIGG	Q5H8A4	637
PGAP1	PIGV	Q9NUD9	627
PGAP1	PIGO	Q8TEQ8	623

IntAct

31 interactions, top by confidence:

A	B	Type	Score
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
SIRT3		psi-mi:“MI:0915”(physical association)	0.400
UPK1A	TMEM223	psi-mi:“MI:0914”(association)	0.350
ISLR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
NCEH1	C1QL1	psi-mi:“MI:0914”(association)	0.350
DISC1	AGRN	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CHRNB4	GPR89A	psi-mi:“MI:0914”(association)	0.350
PTCHD3	ABCD4	psi-mi:“MI:0914”(association)	0.350
TECTA	ZBTB43	psi-mi:“MI:0914”(association)	0.350
NRG1	CHST10	psi-mi:“MI:0914”(association)	0.350
HYOU1	SNX2	psi-mi:“MI:0914”(association)	0.350
NXPE2	PGAP1	psi-mi:“MI:0914”(association)	0.350
MAGT1	PES1	psi-mi:“MI:0914”(association)	0.350
SLC16A8	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC24A3	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
SLC39A13	SCO1	psi-mi:“MI:0914”(association)	0.350
TMEM241	FAAH	psi-mi:“MI:0914”(association)	0.350
E2F3	MYO1C	psi-mi:“MI:0914”(association)	0.350
MYC	PGAP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B5GR44, A0A0D3QS97, A1L314, A4IH88, A7MCS3, B9DFR3, E7F0Z8, F4I107, F4I839, O35298, O54728, O80731, P38566, P38567, P38568, P70683, Q03311, Q0P6H9, Q3TTY0, Q3UUQ7, Q3V5L5, Q4V398, Q5GF25, Q5RBP9, Q60963, Q66GM8, Q6DBP4, Q6E279, Q6NQ51, Q75T13, Q765A7, Q765H6, Q812F3, Q84JS1, Q84WF0, Q8BG22, Q8BXJ9, Q8N2E2, Q93ZR8, Q940J8

Diamond homologs: P0CM50, P0CM51, Q0CIV4, Q0UQV6, Q2H102, Q3UUQ7, Q4P782, Q4WGM4, Q59VP0, Q66J01, Q6BRG1, Q6BZU7, Q6C2Z2, Q6FLY9, Q752Q2, Q75T13, Q765A7, Q7SAM0, Q9W495, P43571, Q1DWP9, Q2USI0, Q5AYC8, Q6CF60, Q6CIN9, Q9UT41

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	19
Uncertain significance	252
Likely benign	151
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101081	NM_024989.4(PGAP1):c.1952+1G>T	Pathogenic
1064599	NM_024989.4(PGAP1):c.1221-3A>G	Pathogenic
1072363	NM_024989.4(PGAP1):c.1952+1G>C	Pathogenic
1980388	NM_024989.4(PGAP1):c.20del (p.Asn7fs)	Pathogenic
2023072	NM_024989.4(PGAP1):c.275del (p.Pro92fs)	Pathogenic
222977	NM_024989.4(PGAP1):c.1572T>A (p.Tyr524Ter)	Pathogenic
222979	NM_024989.4(PGAP1):c.274_276del (p.Pro92del)	Pathogenic
222980	NM_024989.4(PGAP1):c.921_925del (p.Lys308fs)	Pathogenic
222981	NM_024989.4(PGAP1):c.1090-2A>G	Pathogenic
2474508	NM_024989.4(PGAP1):c.2199del (p.Phe734_Leu735insTer)	Pathogenic
2770871	NM_024989.4(PGAP1):c.1867del (p.Cys623fs)	Pathogenic
3233391	NM_024989.4(PGAP1):c.861-2A>G	Pathogenic
3235692	NM_024989.4(PGAP1):c.1546_1549del (p.Val516fs)	Pathogenic
3766104	NM_024989.4(PGAP1):c.1604C>A (p.Ser535Ter)	Pathogenic
4292408	NM_024989.4(PGAP1):c.1869C>A (p.Cys623Ter)	Pathogenic
436299	NM_024989.4(PGAP1):c.927+1G>A	Pathogenic
474988	NM_024989.4(PGAP1):c.1394_1397del (p.Ile465fs)	Pathogenic
474992	NM_024989.4(PGAP1):c.427C>T (p.Gln143Ter)	Pathogenic
503954	NM_024989.4(PGAP1):c.2357_2358insTA (p.Arg786fs)	Pathogenic
57509	GRCh38/hg38 4p15.33-15.31(chr4:14061129-20121834)x1	Pathogenic
58026	GRCh38/hg38 4p15.33-15.31(chr4:14659764-18274924)x3	Pathogenic
814520	GRCh37/hg19 4p16.3-15.2(chr4:68345-27423424)x3	Pathogenic
915318	NM_024989.4(PGAP1):c.776T>G (p.Leu259Ter)	Pathogenic
983141	NM_024989.4(PGAP1):c.1501-2A>G	Pathogenic
983310	GRCh37/hg19 2q32.3-33.1(chr2:197359024-201383462)x1	Pathogenic
985613	NM_024989.4(PGAP1):c.668del (p.Asn223fs)	Pathogenic
1184935	NM_024989.4(PGAP1):c.1089+5del	Likely pathogenic
1477187	NM_024989.4(PGAP1):c.2286+1G>A	Likely pathogenic
1678377	NM_024989.4(PGAP1):c.1162_1163del (p.Ser388fs)	Likely pathogenic
2502370	NM_024989.4(PGAP1):c.289del (p.Ser97fs)	Likely pathogenic

SpliceAI

4370 predictions. Top by Δscore:

Variant	Effect	Δscore
2:196843958:CAGTA:C	donor_gain	1.0000
2:196843962:A:AC	donor_gain	1.0000
2:196843963:C:CC	donor_gain	1.0000
2:196844071:GGATT:G	acceptor_gain	1.0000
2:196844072:GATT:G	acceptor_gain	1.0000
2:196844073:ATT:A	acceptor_gain	1.0000
2:196844074:TT:T	acceptor_gain	1.0000
2:196844074:TTCTA:T	acceptor_loss	1.0000
2:196844075:TCTAT:T	acceptor_loss	1.0000
2:196844076:C:CC	acceptor_gain	1.0000
2:196844077:T:C	acceptor_loss	1.0000
2:196844078:A:C	acceptor_gain	1.0000
2:196844084:CAA:C	acceptor_gain	1.0000
2:196844085:A:T	acceptor_gain	1.0000
2:196844517:AACTT:A	donor_loss	1.0000
2:196844518:ACTTA:A	donor_loss	1.0000
2:196844519:CTTAC:C	donor_loss	1.0000
2:196844520:TTA:T	donor_loss	1.0000
2:196844521:TA:T	donor_loss	1.0000
2:196844522:A:AC	donor_gain	1.0000
2:196844522:A:AT	donor_loss	1.0000
2:196844523:C:CC	donor_gain	1.0000
2:196844523:CCA:C	donor_gain	1.0000
2:196844523:CCAC:C	donor_loss	1.0000
2:196844571:CAAC:C	acceptor_gain	1.0000
2:196844572:AACC:A	acceptor_loss	1.0000
2:196844573:ACC:A	acceptor_loss	1.0000
2:196844574:CCTAA:C	acceptor_loss	1.0000
2:196844575:C:CC	acceptor_gain	1.0000
2:196844575:CTAAG:C	acceptor_loss	1.0000

AlphaMissense

6028 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:196897194:A:C	C288W	1.000
2:196898318:A:G	W287R	1.000
2:196898318:A:T	W287R	1.000
2:196897168:C:G	R297P	0.999
2:196897195:C:A	C288F	0.999
2:196897195:C:G	C288S	0.999
2:196897195:C:T	C288Y	0.999
2:196897196:A:G	C288R	0.999
2:196897196:A:T	C288S	0.999
2:196897197:C:A	W287C	0.999
2:196897197:C:G	W287C	0.999
2:196898331:G:C	H282Q	0.999
2:196898331:G:T	H282Q	0.999
2:196898333:G:C	H282D	0.999
2:196902655:T:A	D246V	0.999
2:196902655:T:G	D246A	0.999
2:196902656:C:G	D246H	0.999
2:196913011:A:G	S174P	0.999
2:196916561:C:G	A112P	0.999
2:196916579:A:G	S106P	0.999
2:196920032:A:G	L89P	0.999
2:196920032:A:T	L89H	0.999
2:196920035:A:T	V88D	0.999
2:196926506:G:C	C37W	0.999
2:196926507:C:G	C37S	0.999
2:196926508:A:G	C37R	0.999
2:196926508:A:T	C37S	0.999
2:196897153:A:G	L302P	0.998
2:196898335:T:A	D281V	0.998
2:196898367:A:C	S270R	0.998

dbSNP variants (sampled 300 via entrez): RS1000022526 (2:196846721 C>T), RS1000057846 (2:196897577 G>A,T), RS1000092781 (2:196921064 T>C), RS1000114234 (2:196861260 C>G), RS1000144970 (2:196836603 T>C), RS1000167645 (2:196888025 C>A,T), RS1000185991 (2:196842937 A>C,G), RS1000253977 (2:196843435 T>C), RS1000266114 (2:196878918 G>A), RS1000427773 (2:196924883 A>G), RS1000433284 (2:196836243 A>G), RS1000456489 (2:196904463 C>T), RS1000506322 (2:196877144 C>T), RS1000575668 (2:196878576 G>A), RS1000616965 (2:196858287 A>T)

Disease associations

OMIM: gene MIM:611655 | disease phenotypes: MIM:615802, MIM:303350, MIM:213300, MIM:249000, MIM:617270, MIM:612313

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 42	Strong	Autosomal recessive
autosomal recessive spastic paraplegia type 67	Supportive	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (9): intellectual disability, autosomal recessive 42 (MONDO:0014348), hereditary spastic paraplegia (MONDO:0019064), neurodevelopmental disorder (MONDO:0700092), Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921), intellectual disability, autosomal recessive 58 (MONDO:0014996), chromosome 2q32-q33 deletion syndrome (MONDO:0012864), autosomal recessive spastic paraplegia type 67 (MONDO:0018419), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (6): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Hereditary spastic paraplegia (Orphanet:685), Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), 2q32q33 deletion syndrome (Orphanet:251019), SATB2-associated syndrome due to a pathogenic variant (Orphanet:576283)

HPO phenotypes

70 total (30 of 70 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000164	Abnormality of the dentition
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000294	Low anterior hairline
HP:0000395	Prominent antihelix
HP:0000400	Macrotia
HP:0000470	Short neck
HP:0000490	Deeply set eye
HP:0000556	Retinal dystrophy
HP:0000582	Upslanted palpebral fissure
HP:0000639	Nystagmus
HP:0000733	Motor stereotypy
HP:0000748	Inappropriate laughter
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000530_2	Parkinson’s disease	3.000000e-09
GCST000874_2	Parkinson’s disease	2.000000e-06
GCST000959_2	Parkinson’s disease	1.000000e-16
GCST001111_3	Current cigarettes per day in chronic obstructive pulmonary disease	5.000000e-06
GCST001430_4	Parkinson’s disease	3.000000e-07
GCST002544_17	Parkinson’s disease	9.000000e-18
GCST002666_1	Interferon alpha levels in systemic lupus erythematosus	1.000000e-06
GCST003984_11	Parkinson’s disease	8.000000e-11
GCST006585_481	Blood protein levels	0.000000e+00
GCST008736_1	Response to beta blocker use in hypertension (systolic blood pressure)	2.000000e-07
GCST009267_20	Dental caries (decayed, missing and filled teeth)	4.000000e-06
GCST009325_99	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-28
GCST009733_140	Urinary metabolite levels in chronic kidney disease	8.000000e-26
GCST009733_150	Urinary metabolite levels in chronic kidney disease	4.000000e-43
GCST010049_8	Parkinson’s disease	4.000000e-07
GCST010991_39	Parkinson’s disease	2.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006517	interferon alpha measurement
EFO:0006944	systolic blood pressure change measurement
EFO:0007766	response to beta blocker
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
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
C567350	Chromosome 2q32-Q33 Deletion Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
Benzo(a)pyrene	increases expression, affects methylation, decreases expression, decreases methylation	4
Aflatoxin B1	affects expression, increases expression, increases methylation	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	affects methylation, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine quinone	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
jinfukang	decreases expression, affects cotreatment, increases expression	1
NSC 689534	increases expression	1
Sunitinib	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	increases expression, affects cotreatment	1
Demecolcine	increases expression	1
Dimethyl Sulfoxide	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia