AGPS

Summary

AGPS (alkylglycerone phosphate synthase, HGNC:327) is a protein-coding gene on chromosome 2q31.2, encoding Alkyldihydroxyacetonephosphate synthase, peroxisomal (O00116). Catalyzes the exchange of the acyl chain in acyl-dihydroxyacetonephosphate (acyl-DHAP) for a long chain fatty alcohol, yielding the first ether linked intermediate, i.e. alkyl-dihydroxyacetonephosphate (alkyl-DHAP), in the pathway of ether lipid biosynthesis.

This gene is a member of the FAD-binding oxidoreductase/transferase type 4 family. It encodes a protein that catalyzes the second step of ether lipid biosynthesis in which acyl-dihydroxyacetonephosphate (DHAP) is converted to alkyl-DHAP by the addition of a long chain alcohol and the removal of a long-chain acid anion. The protein is localized to the inner aspect of the peroxisomal membrane and requires FAD as a cofactor. Mutations in this gene have been associated with rhizomelic chondrodysplasia punctata, type 3 and Zellweger syndrome.

Source: NCBI Gene 8540 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alkylglycerone-phosphate synthase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 823 total — 25 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes
• MANE Select transcript: NM_003659

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:327
Approved symbol	AGPS
Name	alkylglycerone phosphate synthase
Location	2q31.2
Locus type	gene with protein product
Status	Approved
Aliases	ADHAPS, ADAS, ALDHPSY, ADPS, ADAP-S
Ensembl gene	ENSG00000018510
Ensembl biotype	protein_coding
OMIM	603051
Entrez	8540

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 18 protein_coding, 8 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000264167, ENST00000409888, ENST00000460342, ENST00000637633, ENST00000642466, ENST00000679421, ENST00000679459, ENST00000679478, ENST00000679639, ENST00000679994, ENST00000680028, ENST00000680155, ENST00000680390, ENST00000680677, ENST00000680705, ENST00000680770, ENST00000680893, ENST00000680910, ENST00000681028, ENST00000681032, ENST00000681300, ENST00000681449, ENST00000681565, ENST00000681752, ENST00000681891, ENST00000884688, ENST00000884689, ENST00000927418, ENST00000927419, ENST00000927420, ENST00000927421, ENST00000927422, ENST00000927423

RefSeq mRNA: 1 — MANE Select: NM_003659 NM_003659

CCDS: CCDS2275

Canonical transcript exons

ENST00000264167 — 20 exons

Exon	Start	End
ENSE00000782579	177434327	177434417
ENSE00000782583	177442407	177442486
ENSE00000782584	177445546	177445626
ENSE00000782586	177468416	177468524
ENSE00000782587	177482059	177482186
ENSE00000782588	177493148	177493199
ENSE00000782591	177507970	177508031
ENSE00000782592	177513819	177513908
ENSE00000964627	177499618	177499730
ENSE00000964628	177505506	177505575
ENSE00000964629	177521269	177521368
ENSE00000964630	177523748	177523805
ENSE00000964631	177538074	177543834
ENSE00001021889	177461893	177462018
ENSE00001021894	177392773	177393049
ENSE00001261918	177440965	177441036
ENSE00001261926	177436980	177437054
ENSE00001261932	177436764	177436884
ENSE00002451715	177420269	177420358
ENSE00002727446	177497689	177497765

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 91.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.0655 / max 1770.1024, expressed in 1734 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23904	64.0397	1734
23907	0.0258	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	91.95	gold quality
calcaneal tendon	UBERON:0003701	91.58	gold quality
tendon	UBERON:0000043	90.77	gold quality
adrenal tissue	UBERON:0018303	89.54	gold quality
male germ cell	CL:0000015	89.28	gold quality
rectum	UBERON:0001052	89.12	gold quality
tendon of biceps brachii	UBERON:0008188	89.04	gold quality
colonic epithelium	UBERON:0000397	88.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.28	gold quality
bone marrow	UBERON:0002371	88.18	gold quality
colonic mucosa	UBERON:0000317	88.08	gold quality
monocyte	CL:0000576	88.00	gold quality
islet of Langerhans	UBERON:0000006	88.00	gold quality
mononuclear cell	CL:0000842	87.67	gold quality
leukocyte	CL:0000738	87.35	gold quality
bone marrow cell	CL:0002092	87.32	gold quality
secondary oocyte	CL:0000655	86.62	gold quality
bone element	UBERON:0001474	86.19	gold quality
endometrium	UBERON:0001295	85.81	gold quality
endothelial cell	CL:0000115	85.66	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.59	gold quality
ventricular zone	UBERON:0003053	85.23	gold quality
cortical plate	UBERON:0005343	85.07	gold quality
embryo	UBERON:0000922	85.06	gold quality
ganglionic eminence	UBERON:0004023	84.82	gold quality
germinal epithelium of ovary	UBERON:0001304	84.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.51	gold quality
oocyte	CL:0000023	84.35	gold quality
jejunal mucosa	UBERON:0000399	84.26	gold quality
stromal cell of endometrium	CL:0002255	84.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

248 targeting AGPS, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
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-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Literature-anchored findings (GeneRIF, showing 8)

• Defect of ADAPS expression was also assessed by immunoblot (PMID:18571506)
• Novel mutations in AGPS (alkylglycerone-phosphate synthase) cause rhizomelic chondrodysplasia punctata (RCDP) type 3. (PMID:21990100)
• AGPS, in addition to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer. (PMID:23980144)
• AGPS overexpression could be a causation of chemotherapy agent resistance of cancer cells. AGPS silencing could lead to drug uptake and cell cycle arrest and apoptotic cell death. (PMID:24815474)
• Results demonstrated that AGPS negatively regulated the invasion potential of glioma and hepatic carcinoma cells by modulating the expression of relevant genes and activity of the MAPK pathway. (PMID:24841318)
• we optimized the BITC construction targeting alkylglycerone phosphate synthase (AGPS) by computer-aided design, and the derivants also showed anti-tumor potential in vitro. (PMID:25542233)
• Mass Spectrometry and Computer Simulation Predict the Interactions of AGPS and HNRNPK in Glioma. (PMID:34621897)
• TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression. (PMID:38200609)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	agps	ENSDARG00000042821
mus_musculus	Agps	ENSMUSG00000042410
rattus_norvegicus	Agps	ENSRNOG00000001547
drosophila_melanogaster	Agps	FBGN0033983
caenorhabditis_elegans		WBGENE00000081

Paralogs (2): LDHD (ENSG00000166816), D2HGDH (ENSG00000180902)

Protein

Protein identifiers

Alkyldihydroxyacetonephosphate synthase, peroxisomal — O00116 (reviewed: O00116)

Alternative names: Aging-associated gene 5 protein, Alkylglycerone-phosphate synthase

All UniProt accessions (12): O00116, A0A1B0GWA2, A0A2R8YEL0, A0A7P0T857, A0A7P0T8Q7, A0A7P0T984, A0A7P0T9C9, A0A7P0TA54, A0A7P0TAL3, A0A7P0TAU9, B7Z3Q4, B8ZZ81

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the exchange of the acyl chain in acyl-dihydroxyacetonephosphate (acyl-DHAP) for a long chain fatty alcohol, yielding the first ether linked intermediate, i.e. alkyl-dihydroxyacetonephosphate (alkyl-DHAP), in the pathway of ether lipid biosynthesis.

Subunit / interactions. Homodimer.

Subcellular location. Peroxisome membrane. Peroxisome.

Disease relevance. Rhizomelic chondrodysplasia punctata 3 (RCDP3) [MIM:600121] A form of rhizomelic chondrodysplasia punctata, a disease characterized by severely disturbed endochondral bone formation, rhizomelic shortening of femur and humerus, vertebral disorders, dwarfism, cataract, cutaneous lesions, facial dysmorphism, and severe intellectual disability with spasticity. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycerolipid metabolism; ether lipid biosynthesis.

Similarity. Belongs to the FAD-binding oxidoreductase/transferase type 4 family.

RefSeq proteins (1): NP_003650* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004113	FAD-bd_oxidored_4_C	Domain
IPR006094	Oxid_FAD_bind_N	Domain
IPR016164	FAD-linked_Oxase-like_C	Homologous_superfamily
IPR016166	FAD-bd_PCMH	Domain
IPR016167	FAD-bd_PCMH_sub1	Homologous_superfamily
IPR016169	FAD-bd_PCMH_sub2	Homologous_superfamily
IPR016171	Vanillyl_alc_oxidase_C-sub2	Homologous_superfamily
IPR025650	Alkyl-DHAP_Synthase	Family
IPR036318	FAD-bd_PCMH-like_sf	Homologous_superfamily

Pfam: PF01565, PF02913

Enzyme classification (BRENDA):

• EC 2.5.1.26 — alkylglycerone-phosphate synthase (BRENDA: 13 organisms, 17 substrates, 17 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HEXADECANOL	0.04–0.1	5
PALMITOYLDIHYDROXYACETONE PHOSPHATE	0.045–0.1	3
HEXADECYLDIHYDROXYACETONE PHOSPHATE	0.115–0.192	2
OCTADECANOL	0.038	1

Catalyzed reactions (Rhea), 3 shown:

• a long chain fatty alcohol + a 1-acylglycerone 3-phosphate = a 1-O-alkylglycerone 3-phosphate + a long-chain fatty acid + H(+) (RHEA:36171)
• hexadecan-1-ol + 1-hexadecanoylglycerone 3-phosphate = 1-O-hexadecylglycerone 3-phosphate + hexadecanoate + H(+) (RHEA:40659)
• 1-hexadecanoylglycerone 3-phosphate + a long-chain fatty acid = a 1-acylglycerone 3-phosphate + hexadecanoate (RHEA:40727)

UniProt features (26 total): sequence variant 6, binding site 5, modified residue 4, region of interest 4, compositionally biased region 2, transit peptide 1, chain 1, site 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00116-F1	89.27	0.82

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 (2): 419 (important for enzyme activity); 578 (proton donor/acceptor)

Ligand- & substrate-binding residues (5): 234–240; 303–309; 316–319; 368–374; 515

Post-translational modifications (4): 65, 74, 102, 347

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-75896	Plasmalogen biosynthesis
R-HSA-9033241	Peroxisomal protein import
R-HSA-9033500	TYSND1 cleaves peroxisomal proteins
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8848584	Wax and plasmalogen biosynthesis
R-HSA-9609507	Protein localization

MSigDB gene sets: 239 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_ATRX, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, TGACCTY_ERR1_Q2, COUP_01, HNF4_DR1_Q3, PPAR_DR1_Q2, GOBP_LIPID_METABOLIC_PROCESS, MORF_RAP1A, GOBP_LIPID_BIOSYNTHETIC_PROCESS, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, GOCC_MICROBODY_MEMBRANE, BECKER_TAMOXIFEN_RESISTANCE_DN

GO Biological Process (3): lipid biosynthetic process (GO:0008610), ether lipid biosynthetic process (GO:0008611), lipid metabolic process (GO:0006629)

GO Molecular Function (6): alkylglycerone-phosphate synthase activity (GO:0008609), FAD binding (GO:0071949), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), flavin adenine dinucleotide binding (GO:0050660)

GO Cellular Component (6): mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Wax and plasmalogen biosynthesis	1
Protein localization	1
Peroxisomal protein import	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
peroxisome	2
cellular anatomical structure	2
lipid metabolic process	1
biosynthetic process	1
lipid biosynthetic process	1
ether lipid metabolic process	1
glycerol ether biosynthetic process	1
primary metabolic process	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
flavin adenine dinucleotide binding	1
molecular_function	1
binding	1
catalytic activity	1
nucleotide binding	1
anion binding	1
intracellular membrane-bounded organelle	1
microbody	1
microbody membrane	1
microbody lumen	1

Protein interactions and networks

STRING

2358 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGPS	GNPAT	O15228	979
AGPS	PEX7	O00628	922
AGPS	PEX12	O00623	866
AGPS	PEX10	O60683	860
AGPS	PEX16	Q9Y5Y5	856
AGPS	PEX3	P56589	855
AGPS	PEX19	P40855	852
AGPS	PEX5	P50542	849
AGPS	FAR1	Q8WVX9	841
AGPS	PEX14	O75381	828
AGPS	PEX13	Q92968	817
AGPS	PEX5L	Q8IYB4	808
AGPS	PEX6	Q13608	806
AGPS	PEX26	Q7Z412	779
AGPS	PEX2	P28328	763

IntAct

64 interactions, top by confidence:

A	B	Type	Score
GORASP1	AGPS	psi-mi:“MI:0915”(physical association)	0.780
AGPS	GORASP1	psi-mi:“MI:0915”(physical association)	0.780
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
rep	AGPS	psi-mi:“MI:0914”(association)	0.530
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
vpr	AGPS	psi-mi:“MI:0914”(association)	0.460
CAT	NUDT19	psi-mi:“MI:0914”(association)	0.420
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
Cdca5	ATP5MF-PTCD1	psi-mi:“MI:0914”(association)	0.350
CHORDC1	SSR3	psi-mi:“MI:0914”(association)	0.350
PARD6B	PARD3	psi-mi:“MI:0914”(association)	0.350
Sgo2a	GPA33	psi-mi:“MI:0914”(association)	0.350
Septin6	SEPTIN10	psi-mi:“MI:0914”(association)	0.350
EMC2	TBL2	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
M2	AGPS	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (234): GORASP1 (Two-hybrid), AGPS (Affinity Capture-MS), AGPS (Co-fractionation), AGPS (Co-fractionation), LMAN1 (Co-fractionation), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS), AGPS (Affinity Capture-MS)

ESM2 similar proteins: A1L258, B5DEQ3, B7ZMP1, B8B7X6, D4AAT7, F1QXM5, O00116, O04015, O04226, O23240, O45218, O46504, O65361, P31754, P32232, P32296, P46681, P52624, P54887, P54888, P84850, P87228, P97275, Q01415, Q1JPD3, Q3KRD0, Q5M7W7, Q5R6J8, Q5R824, Q68FH4, Q6PI48, Q7TNG8, Q7TSQ8, Q7XI14, Q86WU2, Q8BIP0, Q8C0I1, Q8CIM3, Q8IW45, Q8NCN5

Diamond homologs: O00116, O45218, O96759, O97157, P97275, P9WIT0, P9WIT1, Q8C0I1, Q9EQR2, Q9V778, O23240, A1L258, A4VGK4, D4MUV9, H6LBS1, O29853, P0AEP9, P0AEQ0, P0DV35, P84850, P94535, Q8CIM3, Q8N465, O47881, P43485, Q0CZH0, Q2QXY1, Q2RAP0, Q752Y3, Q7SGY1, Q9SU56, D4AS41, P10867, P32891, P52073, Q7TNG8, Q86WU2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Peroxisomal protein import	5	24.0×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to reactive oxygen species	5	45.7×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	22
Uncertain significance	203
Likely benign	456
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
147705	GRCh38/hg38 2q31.1-32.2(chr2:174634502-189000964)x1	Pathogenic
155417	GRCh38/hg38 2q31.1-32.3(chr2:176086763-193201970)x1	Pathogenic
1708467	GRCh37/hg19 2q31.2(chr2:178085640-178407456)x1	Pathogenic
1808725	GRCh37/hg19 2q31.1-31.3(chr2:175143352-180999636)x1	Pathogenic
252975	GRCh37/hg19 2q31.1-32.3(chr2:177315153-196375520)x1	Pathogenic
3247478	NC_000002.11:g.(?178257518)(179914668_?)del	Pathogenic
3366567	NC_000002.11:g.(178362494_178364345)_(178372760_178378546)del	Pathogenic
35469	NM_003659.4(AGPS):c.1703C>T (p.Thr568Met)	Pathogenic
4292356	NM_003659.4(AGPS):c.638-1G>A	Pathogenic
4292606	NM_003659.4(AGPS):c.1736dup (p.Tyr580fs)	Pathogenic
4682546	GRCh37/hg19 2q31.1-32.2(chr2:171436894-189531954)x1	Pathogenic
4693459	NM_003659.4(AGPS):c.1543C>T (p.Arg515Ter)	Pathogenic
4710499	NM_003659.4(AGPS):c.549del (p.Phe184fs)	Pathogenic
4808951	NM_003659.4(AGPS):c.1663_1666dup (p.Gly556fs)	Pathogenic
562664	GRCh37/hg19 2q31.1-31.2(chr2:173741558-178416381)x1	Pathogenic
57130	GRCh38/hg38 2q31.1-31.2(chr2:172779876-177598000)x1	Pathogenic
58767	GRCh38/hg38 2q31.1-31.2(chr2:173408061-177702487)x1	Pathogenic
58770	GRCh38/hg38 2q31.1-33.1(chr2:176304445-202039790)x1	Pathogenic
625773	GRCh37/hg19 2q31.1-31.2(chr2:176794846-178494259)	Pathogenic
6647	NM_003659.4(AGPS):c.1406T>C (p.Leu469Pro)	Pathogenic
685829	GRCh37/hg19 2q31.1-32.1(chr2:173538954-186401606)x1	Pathogenic
688324	GRCh37/hg19 2q31.1-31.2(chr2:176310551-179092634)x1	Pathogenic
814337	GRCh37/hg19 2q24.2-34(chr2:163233162-211927188)x3	Pathogenic
814347	GRCh37/hg19 2q31.1-32.3(chr2:174690039-195521582)x1	Pathogenic
983184	GRCh37/hg19 2q31.2-37.3(chr2:178397959-243007457)x3	Pathogenic
1120083	NM_003659.4(AGPS):c.1037_1043del (p.Glu346fs)	Likely pathogenic
1418693	NM_003659.4(AGPS):c.1233+1G>A	Likely pathogenic
2504001	NM_003659.4(AGPS):c.1658_1659del (p.Lys553fs)	Likely pathogenic
2674880	NM_003659.4(AGPS):c.288G>A (p.Trp96Ter)	Likely pathogenic
2674887	NM_003659.4(AGPS):c.1608-1G>A	Likely pathogenic

SpliceAI

3620 predictions. Top by Δscore:

Variant	Effect	Δscore
2:177393047:GCG:G	donor_gain	1.0000
2:177393049:GGTG:G	donor_loss	1.0000
2:177393050:G:GA	donor_loss	1.0000
2:177393050:G:GG	donor_gain	1.0000
2:177393051:T:G	donor_loss	1.0000
2:177420267:A:AG	acceptor_gain	1.0000
2:177420268:G:GG	acceptor_gain	1.0000
2:177434322:CTTA:C	acceptor_loss	1.0000
2:177434323:TTA:T	acceptor_loss	1.0000
2:177434324:TA:T	acceptor_loss	1.0000
2:177434325:A:AG	acceptor_gain	1.0000
2:177434325:A:C	acceptor_loss	1.0000
2:177434326:G:A	acceptor_loss	1.0000
2:177434326:G:GG	acceptor_gain	1.0000
2:177434326:GGT:G	acceptor_gain	1.0000
2:177434414:TAAAG:T	donor_loss	1.0000
2:177434415:AAAGT:A	donor_loss	1.0000
2:177434416:AA:A	donor_gain	1.0000
2:177434416:AAGT:A	donor_loss	1.0000
2:177434417:AGTA:A	donor_loss	1.0000
2:177434418:G:GG	donor_gain	1.0000
2:177434418:GTAA:G	donor_loss	1.0000
2:177434419:TAAG:T	donor_loss	1.0000
2:177436759:TCTA:T	acceptor_loss	1.0000
2:177436761:TA:T	acceptor_loss	1.0000
2:177436761:TAGGC:T	acceptor_gain	1.0000
2:177436762:A:AG	acceptor_gain	1.0000
2:177436762:A:T	acceptor_loss	1.0000
2:177436762:AGGCA:A	acceptor_gain	1.0000
2:177436763:G:GT	acceptor_gain	1.0000

AlphaMissense

4303 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:177461894:T:C	L291P	1.000
2:177461929:G:C	D303H	1.000
2:177461944:A:C	S308R	1.000
2:177461946:T:A	S308R	1.000
2:177461946:T:G	S308R	1.000
2:177461959:T:A	W313R	1.000
2:177461959:T:C	W313R	1.000
2:177482127:T:C	S392P	1.000
2:177499718:C:A	A488D	1.000
2:177505508:G:A	G493E	1.000
2:177505532:G:A	G501E	1.000
2:177508024:T:A	W534R	1.000
2:177508024:T:C	W534R	1.000
2:177508026:G:C	W534C	1.000
2:177508026:G:T	W534C	1.000
2:177521299:T:G	C576W	1.000
2:177523796:C:G	H616D	1.000
2:177523799:C:G	H617D	1.000
2:177420294:T:A	W96R	0.999
2:177420294:T:C	W96R	0.999
2:177420296:G:C	W96C	0.999
2:177420296:G:T	W96C	0.999
2:177420298:G:A	G97E	0.999
2:177437043:T:A	V209D	0.999
2:177445583:C:A	A276D	0.999
2:177445598:G:A	G281D	0.999
2:177445607:G:A	G284E	0.999
2:177461918:G:A	G299D	0.999
2:177461920:C:G	H300D	0.999
2:177461927:C:A	P302Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000004439 (2:177484872 C>T), RS1000041365 (2:177491631 G>A,T), RS1000079321 (2:177540315 T>C), RS1000110352 (2:177454619 A>G), RS1000170984 (2:177513156 G>A), RS1000191785 (2:177465675 A>C), RS1000209265 (2:177434246 C>G), RS1000247609 (2:177520417 A>G), RS1000263002 (2:177498974 C>T), RS1000264436 (2:177489850 A>C), RS1000327217 (2:177537211 T>C), RS1000399615 (2:177505427 T>C), RS1000406850 (2:177401342 C>G,T), RS1000415686 (2:177483536 A>C), RS1000465713 (2:177394046 A>G)

Disease associations

OMIM: gene MIM:603051 | disease phenotypes: MIM:600121, MIM:215100

GenCC curated gene-disease

Disease	Classification	Inheritance
rhizomelic chondrodysplasia punctata type 3	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
alkylglycerone-phosphate synthase deficiency	Definitive	AR

Mondo (2): rhizomelic chondrodysplasia punctata type 3 (MONDO:0010823), rhizomelic chondrodysplasia punctata (MONDO:0015776)

Orphanet (2): Rhizomelic chondrodysplasia punctata (Orphanet:177), Rhizomelic chondrodysplasia punctata type 3 (Orphanet:309803)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001508	Failure to thrive
HP:0003097	Short femur
HP:0005792	Short humerus
HP:0008873	Disproportionate short-limb short stature
HP:0008905	Rhizomelia
HP:0010655	Epiphyseal stippling
HP:6000427	Reduced alkyl-dihydroxyacetonephosphate synthase activity in cultured fibroblasts

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008163_77	Height	6.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018902	Chondrodysplasia Punctata, Rhizomelic	C05.116.099.708.195.200; C16.320.565.663.265; C18.452.648.663.265
C537608	Rhizomelic chondrodysplasia punctata, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295643 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	Kd	1.596	nM	CHEMBL3752910
8.80	ED50	1.596	nM	CHEMBL3752910
6.31	Kd	485.7	nM	CHEMBL5653589
6.31	ED50	485.7	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 35 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147819: Binding affinity to human AGPS incubated for 45 mins by Kinobead based pull down assay	kd	0.0016	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147819: Binding affinity to human AGPS incubated for 45 mins by Kinobead based pull down assay	kd	0.4857	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	affects expression	1
sodium arsenate	decreases expression	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118559	Binding	Binding affinity to AGPS in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05969977	PHASE1	UNKNOWN	A First-in-Human Phase 1 Study of Plasmalogen Precursor PPI-1011 in Healthy Adult Volunteers to Assess Safety, Tolerability, and Pharmacokinetics
NCT04569162	Not specified	RECRUITING	Rhizomelic Chondrodysplasia Punctata Registry
NCT04031287	Not specified	UNKNOWN	RCDP Natural History Study