PGAP3

Summary

PGAP3 (post-GPI attachment to proteins phospholipase 3, HGNC:23719) is a protein-coding gene on chromosome 17q12, encoding GPI-specific phospholipase A2-like PGAP3 (Q96FM1). Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.

This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 93210 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperphosphatasia with intellectual disability syndrome 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 249 total — 26 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 79
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_033419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23719
Approved symbol	PGAP3
Name	post-GPI attachment to proteins phospholipase 3
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	MGC9753, CAB2, PP1498, PER1
Ensembl gene	ENSG00000161395
Ensembl biotype	protein_coding
OMIM	611801
Entrez	93210

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000300658, ENST00000309862, ENST00000378011, ENST00000429199, ENST00000577337, ENST00000579146, ENST00000580898, ENST00000582276, ENST00000584620, ENST00000584856, ENST00000619169

RefSeq mRNA: 6 — MANE Select: NM_033419 NM_001291726, NM_001291728, NM_001291730, NM_001291732, NM_001291733, NM_033419

CCDS: CCDS32641, CCDS77013, CCDS77014, CCDS77015

Canonical transcript exons

ENST00000300658 — 8 exons

Exon	Start	End
ENSE00003502656	39684597	39684749
ENSE00003508260	39673993	39674054
ENSE00003534702	39673514	39673650
ENSE00003588456	39673051	39673255
ENSE00003599710	39687834	39688057
ENSE00003609544	39671122	39672866
ENSE00003658553	39674617	39674679
ENSE00003661347	39685922	39686019

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9365 / max 39.3968, expressed in 1717 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165616	5.9365	1717

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.00	gold quality
left lobe of thyroid gland	UBERON:0001120	92.36	gold quality
right lobe of thyroid gland	UBERON:0001119	92.23	gold quality
thyroid gland	UBERON:0002046	91.75	gold quality
mucosa of transverse colon	UBERON:0004991	91.38	gold quality
lower esophagus mucosa	UBERON:0035834	90.70	gold quality
granulocyte	CL:0000094	90.64	gold quality
right uterine tube	UBERON:0001302	90.00	gold quality
nasal cavity epithelium	UBERON:0005384	89.93	gold quality
right lobe of liver	UBERON:0001114	89.75	gold quality
metanephros cortex	UBERON:0010533	89.75	gold quality
minor salivary gland	UBERON:0001830	89.72	gold quality
olfactory bulb	UBERON:0002264	89.68	gold quality
body of pancreas	UBERON:0001150	89.49	gold quality
skin of leg	UBERON:0001511	89.44	gold quality
saliva-secreting gland	UBERON:0001044	89.31	gold quality
ileal mucosa	UBERON:0000331	89.23	gold quality
mouth mucosa	UBERON:0003729	89.12	gold quality
pharyngeal mucosa	UBERON:0000355	88.98	gold quality
esophagus mucosa	UBERON:0002469	88.78	gold quality
transverse colon	UBERON:0001157	88.51	gold quality
skin of abdomen	UBERON:0001416	88.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.00	gold quality
renal medulla	UBERON:0000362	87.77	gold quality
cervix squamous epithelium	UBERON:0006922	87.56	gold quality
zone of skin	UBERON:0000014	87.50	gold quality
nasal cavity mucosa	UBERON:0001826	87.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.26	gold quality
nipple	UBERON:0002030	87.22	gold quality
apex of heart	UBERON:0002098	87.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting PGAP3, 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-6798-5P	100.00	65.77	699
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-16-1-3P	98.70	69.23	1538

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 13)

• MGC9753, consisting of eight exons, clustered with PPP1R1B, STARD3, TCAP, PNMT, ERBB2, MGC14832 and GRB7 genes within the 120-kb region of chromosome 17q12; PPP1R1B, STARD3, MGC9753, ERBB2 and GRB7 genes are co-amplified in several cases of gastric cancer (PMID:12739007)
• Oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-C17orf37-GRB7 amplicon at human chromosome 17q12 is closely linked to evolutionary recombination hotspot around the GSDML-GSDM locus. (PMID:15010812)
• These findings revealed the association of PERLD1 as a novel asthma candidate gene and reinforced the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma. (PMID:22188591)
• Data show that glycosylphosphatidylinositol-anchored proteins (GPI-APs) are secreted into the medium by cells overexpressing PGAP3. (PMID:23615438)
• Impairment of PGAP3 causes a subtype of hyperphosphatasia with intellectual disabilities, a congenital disorder of glycosylation that is also referred to as Mabry syndrome. (PMID:24439110)
• A screening approach with sequence specific baits for transcripts of genes of the GPI pathway identified pathogenic noncoding mutations in PGAP3 subtype of hyperphosphatasia with mental retardation syndrome. Besides five missense mutations, an intronic mutation was found causing an aberrant splice product and a mutation in the 3’UTR that is associated with substantially lower mRNA levels. (PMID:27120253)
• Data show that biallelic loss of function mutations in the post-GPI attachment to proteins 3 (PGAP3) gene were detected in all patients. (PMID:28390064)
• The Asthma-associated PER1-like domain-containing protein 1 (PERLD1) Haplotype Influences Soluble Glycosylphosphatidylinositol Anchor Protein (sGPI-AP) Levels in Serum and Immune Cell Proliferation. (PMID:31959860)
• Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients. (PMID:32845056)
• The novel circular RNA circ-PGAP3 retards cervical cancer growth by regulating the miR-769-5p/p53 axis. (PMID:33591461)
• Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene. (PMID:34051734)
• Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases. (PMID:37647829)
• High PGAP3 expression is associated with lymph node metastasis and low CD8[+]T cell in patients with HER2[+] breast cancer. (PMID:37839361)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgap3	ENSDARG00000057531
mus_musculus	Pgap3	ENSMUSG00000038208
rattus_norvegicus	Pgap3	ENSRNOG00000046143
drosophila_melanogaster	PGAP3	FBGN0033088
caenorhabditis_elegans		WBGENE00019806

Protein

Protein identifiers

GPI-specific phospholipase A2-like PGAP3 — Q96FM1 (reviewed: Q96FM1)

Alternative names: COS16 homolog, Gene coamplified with ERBB2 protein, PER1-like domain-containing protein 1, Post-GPI attachment to proteins factor 3

All UniProt accessions (6): A0A087WTP0, Q96FM1, J3KTJ2, J3QKU0, J3QQL0, J3QRN7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain. May catalyze the first step of the fatty acid remodeling, by removing the unsaturated acyl chain at sn-2 of inositol phosphate, generating a lyso-GPI intermediate. The fatty acid remodeling steps is critical for the integration of GPI-APs into lipid rafts.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Ubiquitously expressed, with highest levels in thyroid and placenta.

Disease relevance. Hyperphosphatasia with impaired intellectual development syndrome 4 (HPMRS4) [MIM:615716] An autosomal recessive neurologic disorder characterized by profound developmental delay, severe intellectual disability, no speech, psychomotor delay, postnatal microcephaly, and elevated serum alkaline phosphatase. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. When transfected in S.cerevisiae, it can complement the absence of yeast of PER1 protein, suggesting a conserved role in lipid remodeling steps of GPI-anchor maturation.

Similarity. Belongs to the PGAP3 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96FM1-1	1	yes
Q96FM1-2	2
Q96FM1-3	3

RefSeq proteins (6): NP_001278655, NP_001278657, NP_001278659, NP_001278661, NP_001278662, NP_219487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007217	Per1-like	Family

Pfam: PF04080

Catalyzed reactions (Rhea), 1 shown:

• [protein]-C-terminal carboxyl phosphoethanolamide-GPI(deacylinositol-H7) + H2O = [protein]-C-terminal carboxyl phosphoethanolamide-lysoGPI(deacylinositol-H7) + a fatty acid + H(+) (RHEA:83847)

UniProt features (26 total): topological domain 8, transmembrane region 7, sequence variant 4, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FM1-F1	93.17	0.88

Functional residue map

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

Glycosylation sites (1): 40

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 684 (showing top): GOBP_CIRCADIAN_RHYTHM, ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOBP_PHOTOPERIODISM, ENK_UV_RESPONSE_KERATINOCYTE_UP, AMIT_EGF_RESPONSE_60_HELA, GCANCTGNY_MYOD_Q6

GO Biological Process (2): GPI anchor metabolic process (GO:0006505), GPI anchor biosynthetic process (GO:0006506)

GO Molecular Function (3): hydrolase activity, acting on ester bonds (GO:0016788), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), cytoplasmic vesicle (GO:0031410), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
glycerophospholipid metabolic process	1
glycolipid metabolic process	1
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
GPI anchored protein biosynthesis	1
hydrolase activity	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular vesicle	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

732 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGAP3	PGAP2	Q9UHJ9	859
PGAP3	STARD3	Q14849	803
PGAP3	PGAP1	Q75T13	791
PGAP3	PIGW	Q7Z7B1	772
PGAP3	MIEN1	Q9BRT3	766
PGAP3	PIGV	Q9NUD9	739
PGAP3	PIGO	Q8TEQ8	736
PGAP3	GRB7	Q14451	715
PGAP3	PIGY	Q3MUY2	712
PGAP3	PIGK	Q92643	706
PGAP3	PIGT	Q969N2	704
PGAP3	PIGM	Q9H3S5	702
PGAP3	PIGL	Q9Y2B2	698
PGAP3	TCAP	O15273	688
PGAP3	GSDMB	Q8TAX9	651

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PGAP3	GTF3C3	psi-mi:“MI:0915”(physical association)	0.560
PGAP3	TBRG4	psi-mi:“MI:0915”(physical association)	0.500
PGAP3	CREB3	psi-mi:“MI:0915”(physical association)	0.370
PGAP3	SCAMP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): TBRG4 (Affinity Capture-MS), VKORC1L1 (Affinity Capture-MS), TBRG4 (Affinity Capture-MS), PGAP3 (Affinity Capture-MS), TBRG4 (Affinity Capture-MS), VKORC1L1 (Affinity Capture-MS), ANKRD13A (Affinity Capture-MS), SCAMP3 (Affinity Capture-MS), SPG7 (Affinity Capture-MS), PGAP3 (Affinity Capture-MS), PGAP3 (Affinity Capture-RNA)

ESM2 similar proteins: A2A559, A2V7M9, A6H7B8, A6X919, A7YWP2, A8KBG2, A8WFS8, B2GV22, D4AD75, E1BYA3, F1Q8R9, O08888, O45145, O49639, P25625, P38298, P70245, Q0VFE3, Q15125, Q290J8, Q2ABP2, Q2ABP3, Q3SZ36, Q3TQR0, Q568I2, Q5M9A7, Q60490, Q60WT2, Q68EV0, Q6P0S3, Q753H5, Q7K0P4, Q801D8, Q801G2, Q8C2R7, Q8N4S7, Q8R4X1, Q8T8L8, Q8TDN7, Q91VH1

Diamond homologs: A2A559, A2V7M9, A7YWP2, A8WFS8, Q0VFE3, Q68EV0, Q7K0P4, Q96FM1, Q9P6N9, P25625

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	9
Uncertain significance	83
Likely benign	85
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
125437	NM_033419.5(PGAP3):c.275G>A (p.Gly92Asp)	Pathogenic
125439	NM_033419.5(PGAP3):c.914A>G (p.Asp305Gly)	Pathogenic
125440	NM_033419.5(PGAP3):c.314C>G (p.Pro105Arg)	Pathogenic
1323441	NM_033419.5(PGAP3):c.455G>A (p.Trp152Ter)	Pathogenic
1687230	NM_033419.5(PGAP3):c.452dup (p.Trp152fs)	Pathogenic
2227732	NM_033419.5(PGAP3):c.205A>T (p.Lys69Ter)	Pathogenic
224640	NM_033419.5(PGAP3):c.402dup (p.Met135fs)	Pathogenic
224641	NM_033419.5(PGAP3):c.861G>T (p.Trp287Cys)	Pathogenic
224644	NM_033419.5(PGAP3):c.845A>G (p.Asp282Gly)	Pathogenic
224646	NM_033419.5(PGAP3):c.439dup (p.Leu147fs)	Pathogenic
224647	NM_033419.5(PGAP3):c.511T>C (p.Cys171Arg)	Pathogenic
224648	NM_033419.5(PGAP3):c.842T>C (p.Leu281Pro)	Pathogenic
2752554	NM_033419.5(PGAP3):c.571C>T (p.Gln191Ter)	Pathogenic
3028899	NM_033419.5(PGAP3):c.265C>T (p.Gln89Ter)	Pathogenic
3243213	NC_000017.10:g.(?37840830)(37841022_?)del	Pathogenic
3243214	NC_000017.10:g.(?37842155)(37844267_?)del	Pathogenic
3385330	NM_033419.5(PGAP3):c.355del (p.Leu119fs)	Pathogenic
3670051	NM_033419.5(PGAP3):c.739C>T (p.Gln247Ter)	Pathogenic
3715220	NM_033419.5(PGAP3):c.450dup (p.Phe151fs)	Pathogenic
373293	NM_033419.5(PGAP3):c.694+1G>A	Pathogenic
3775700	NM_033419.5(PGAP3):c.80dup (p.Val28fs)	Pathogenic
496676	NM_033419.5(PGAP3):c.280del (p.Trp94fs)	Pathogenic
520887	NM_033419.5(PGAP3):c.109G>T (p.Glu37Ter)	Pathogenic
522978	NM_033419.5(PGAP3):c.432+1G>A	Pathogenic
620568	NM_033419.5(PGAP3):c.726G>A (p.Trp242Ter)	Pathogenic
982399	NM_033419.5(PGAP3):c.75_81dup (p.Val28Ter)	Pathogenic
1683736	NM_033419.5(PGAP3):c.50_52delinsC (p.Leu17fs)	Likely pathogenic
1705418	NM_033419.5(PGAP3):c.314C>A (p.Pro105Gln)	Likely pathogenic
1802697	NM_033419.5(PGAP3):c.896dup (p.Ser300fs)	Likely pathogenic
3068561	NM_033419.5(PGAP3):c.43dup (p.Ala15fs)	Likely pathogenic

SpliceAI

4701 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39672862:GAAAG:G	acceptor_gain	1.0000
17:39672865:AG:A	acceptor_gain	1.0000
17:39672865:AGC:A	acceptor_loss	1.0000
17:39672867:C:CA	acceptor_loss	1.0000
17:39672867:C:CC	acceptor_gain	1.0000
17:39673046:CCCA:C	donor_loss	1.0000
17:39673264:C:CT	acceptor_gain	1.0000
17:39673264:C:T	acceptor_gain	1.0000
17:39673265:A:T	acceptor_gain	1.0000
17:39684746:GCCA:G	acceptor_gain	1.0000
17:39684747:CCA:C	acceptor_gain	1.0000
17:39684747:CCAC:C	acceptor_gain	1.0000
17:39684748:CA:C	acceptor_gain	1.0000
17:39684748:CAC:C	acceptor_gain	1.0000
17:39684750:C:CC	acceptor_gain	1.0000
17:39687828:GCTTA:G	donor_loss	1.0000
17:39687829:CTTAC:C	donor_loss	1.0000
17:39687833:CCTG:C	donor_gain	1.0000
17:8141336:CAGGC:C	acceptor_gain	1.0000
17:8141340:CCT:C	acceptor_gain	1.0000
17:8141341:C:CA	acceptor_loss	1.0000
17:8141341:C:CC	acceptor_gain	1.0000
17:8141342:T:C	acceptor_gain	1.0000
17:8141342:T:TC	acceptor_gain	1.0000
17:8141962:A:T	acceptor_gain	1.0000
17:8142265:TCACC:T	donor_loss	1.0000
17:8142266:CACCT:C	donor_loss	1.0000
17:8142267:ACC:A	donor_loss	1.0000
17:8142268:C:CG	donor_loss	1.0000
17:8142455:CTGC:C	acceptor_gain	1.0000

AlphaMissense

2075 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39685931:G:C	F90L	0.999
17:39685931:G:T	F90L	0.999
17:39685933:A:G	F90L	0.999
17:39674644:G:C	F156L	0.998
17:39674644:G:T	F156L	0.998
17:39674646:A:G	F156L	0.998
17:39674643:G:C	H157D	0.997
17:39684747:C:A	W94C	0.997
17:39684747:C:G	W94C	0.997
17:39685932:A:C	F90C	0.997
17:39685932:A:G	F90S	0.997
17:39684749:A:G	W94R	0.996
17:39684749:A:T	W94R	0.996
17:39672863:A:C	F301L	0.995
17:39672863:A:T	F301L	0.995
17:39672865:A:G	F301L	0.995
17:39673105:T:A	D282V	0.995
17:39674046:G:C	D168E	0.995
17:39674046:G:T	D168E	0.995
17:39685922:C:A	K93N	0.995
17:39685922:C:G	K93N	0.995
17:39674658:A:G	W152R	0.994
17:39674658:A:T	W152R	0.994
17:39684741:G:C	F96L	0.994
17:39684741:G:T	F96L	0.994
17:39684743:A:G	F96L	0.994
17:39674047:T:A	D168V	0.993
17:39674047:T:G	D168A	0.993
17:39674048:C:G	D168H	0.993
17:39673097:C:G	A285P	0.992

dbSNP variants (sampled 300 via entrez): RS1000173181 (17:39682797 G>A), RS1000294025 (17:39671438 C>G), RS1000434543 (17:39680960 C>T), RS1000783050 (17:39675455 C>T), RS1000868831 (17:39681162 G>A), RS1000931450 (17:39690040 T>C), RS1001285665 (17:39689798 A>G), RS1001615770 (17:39679426 A>C), RS1001625470 (17:39679104 CCTGA>C), RS1001783435 (17:39677162 T>C), RS1001832067 (17:39685544 G>A), RS1001841190 (17:39682567 T>C), RS1001901187 (17:39677382 G>A), RS1001937566 (17:39680763 C>A,T), RS1002012176 (17:39671439 C>A)

Disease associations

OMIM: gene MIM:611801 | disease phenotypes: MIM:615716, MIM:239300

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperphosphatasia with intellectual disability syndrome 4	Definitive	Autosomal recessive
hyperphosphatasia-intellectual disability syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyperphosphatasia with intellectual disability syndrome 4	Definitive	AR

Mondo (2): hyperphosphatasia with intellectual disability syndrome 4 (MONDO:0014318), hyperphosphatasia-intellectual disability syndrome (MONDO:0016596)

Orphanet (1): Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000470	Short neck
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000594	Shallow anterior chamber
HP:0000637	Long palpebral fissure
HP:0000657	Oculomotor apraxia
HP:0000729	Autistic behavior

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST003589_1	Bronchial hyperresponsiveness in asthma	3.000000e-20
GCST005212_9	Asthma	2.000000e-30
GCST005312_39	Menopause (age at onset)	2.000000e-09
GCST006436_5	Triglyceride levels	1.000000e-09
GCST007235_3	Pancreatic ductal adenocarcinoma	1.000000e-06
GCST007564_21	Asthma or allergic disease (pleiotropy)	4.000000e-17
GCST008916_10	Asthma	5.000000e-09
GCST008916_21	Asthma	2.000000e-62
GCST008916_45	Asthma	3.000000e-10
GCST008916_86	Asthma	2.000000e-14
GCST009798_16	Asthma	8.000000e-27
GCST010002_123	Refractive error	1.000000e-24
GCST90011900_147	Serum alkaline phosphatase levels	7.000000e-31
GCST90013406_121	Liver enzyme levels (alkaline phosphatase)	3.000000e-56

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004530	triglyceride measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	4
Benzo(a)pyrene	decreases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
beta-Naphthoflavone	decreases expression	1
Acrylamide	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TC99	HAP1 PGAP3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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