PGAP6

Summary

PGAP6 (post-GPI attachment to proteins 6, HGNC:17205) is a protein-coding gene on chromosome 16p13.3, encoding Post-GPI attachment to proteins factor 6 (Q9HCN3). Involved in the lipid remodeling steps of GPI-anchor maturation.

Predicted to enable phospholipase A2 activity. Predicted to be involved in lipid metabolic process. Located in extracellular exosome and lysosomal membrane.

Source: NCBI Gene 58986 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 249 total
• MANE Select transcript: NM_021259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17205
Approved symbol	PGAP6
Name	post-GPI attachment to proteins 6
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	M83
Ensembl gene	ENSG00000129925
Ensembl biotype	protein_coding
OMIM	619342
Entrez	58986

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000250930, ENST00000424078, ENST00000427313, ENST00000431232, ENST00000448854, ENST00000467452, ENST00000475348, ENST00000476735, ENST00000930879, ENST00000930880, ENST00000930881, ENST00000946604, ENST00000946605, ENST00000946606, ENST00000946607, ENST00000946608

RefSeq mRNA: 1 — MANE Select: NM_021259 NM_021259

CCDS: CCDS10407

Canonical transcript exons

ENST00000431232 — 13 exons

Exon	Start	End
ENSE00000892464	372611	372727
ENSE00000892467	374756	374892
ENSE00000892475	381701	381978
ENSE00001615523	376544	376812
ENSE00001688531	376136	376455
ENSE00001788417	370788	372283
ENSE00003459862	374221	374399
ENSE00003531838	375345	375435
ENSE00003533974	377671	377848
ENSE00003591614	375133	375256
ENSE00003621134	374005	374151
ENSE00003652853	377378	377585
ENSE00003653494	377037	377164

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 97.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.6168 / max 208.2473, expressed in 1795 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155732	12.4135	1787
155731	1.7434	811
155730	0.7720	425
155729	0.4720	289
155728	0.2160	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.12	gold quality
stromal cell of endometrium	CL:0002255	96.95	gold quality
right testis	UBERON:0004534	96.54	gold quality
left testis	UBERON:0004533	96.46	gold quality
mucosa of transverse colon	UBERON:0004991	96.10	gold quality
metanephros cortex	UBERON:0010533	96.02	gold quality
lower esophagus mucosa	UBERON:0035834	95.82	gold quality
granulocyte	CL:0000094	95.78	gold quality
body of stomach	UBERON:0001161	95.72	gold quality
transverse colon	UBERON:0001157	94.61	gold quality
testis	UBERON:0000473	94.54	gold quality
blood	UBERON:0000178	94.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.97	gold quality
apex of heart	UBERON:0002098	93.94	gold quality
gall bladder	UBERON:0002110	93.88	gold quality
upper lobe of left lung	UBERON:0008952	93.82	gold quality
minor salivary gland	UBERON:0001830	93.73	gold quality
pancreas	UBERON:0001264	93.66	gold quality
stomach	UBERON:0000945	93.55	gold quality
adenohypophysis	UBERON:0002196	93.39	gold quality
upper lobe of lung	UBERON:0008948	93.35	gold quality
saliva-secreting gland	UBERON:0001044	93.07	gold quality
small intestine	UBERON:0002108	92.94	gold quality
right lobe of liver	UBERON:0001114	92.79	gold quality
right lung	UBERON:0002167	92.78	gold quality
right lobe of thyroid gland	UBERON:0001119	92.57	gold quality
placenta	UBERON:0001987	92.42	gold quality
left lobe of thyroid gland	UBERON:0001120	92.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.12	gold quality
descending thoracic aorta	UBERON:0002345	92.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting PGAP6, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-3668	98.52	68.76	951

Literature-anchored findings (GeneRIF, showing 3)

• TMEM8A protein localizes in lysosomes in HeLa cells (PMID:21752829)
• PGAP6 plays a critical role in Nodal signaling modulation through CRIPTO shedding. (PMID:27881714)
• PGAP6, a GPI-specific phospholipase A2, has narrow substrate specificity against GPI-anchored proteins. (PMID:32816994)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgap6	ENSDARG00000032795
mus_musculus	Pgap6	ENSMUSG00000024180
rattus_norvegicus	Pgap6	ENSRNOG00000020374

Paralogs (2): TMEM8B (ENSG00000137103), MYMK (ENSG00000187616)

Protein

Protein identifiers

Post-GPI attachment to proteins factor 6 — Q9HCN3 (reviewed: Q9HCN3)

Alternative names: GPI processing phospholipase A2, Protein M83, Transmembrane protein 6, Transmembrane protein 8, Transmembrane protein 8A

All UniProt accessions (5): Q9HCN3, C9J8D7, H0Y5B2, H7C1S0, K4DI83

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the lipid remodeling steps of GPI-anchor maturation. Lipid remodeling steps consist in the generation of 2 saturated fatty chains at the sn-2 position of GPI-anchor proteins (GPI-AP). Has phospholipase A2 activity that removes an acyl-chain at the sn-2 position of GPI-anchors during the remodeling of GPI. Required for the shedding of the GPI-AP CRIPTO, but not CFC1, at the cell surface. Shedding of CRIPTO modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells. Also indirectly involved in the translocation of RAC1 from the cytosol to the plasma membrane by maintaining the steady state amount of CAV1-enriched plasma membrane subdomains, stabilizing RAC1 at the plasma membrane. In contrast to myomaker (TMEM8C), has no fusogenic activity.

Subcellular location. Cell membrane. Lysosome membrane.

Tissue specificity. Expressed in pancreas, placenta, spleen, liver, kidney, bone marrow, peripheral blood leukocytes and tonsil.

Post-translational modifications. Glycosylated.

Induction. Repressed during activation of CD4+ and CD8+ T-lymphocytes.

Similarity. Belongs to the TMEM8 family.

RefSeq proteins (1): NP_067082* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR021910	NGX6/PGAP6/MYMK	Family

Pfam: PF12036

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)

UniProt features (37 total): topological domain 8, transmembrane region 7, mutagenesis site 5, glycosylation site 3, disulfide bond 3, sequence variant 3, sequence conflict 3, signal peptide 1, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCN3-F1	81.39	0.53

Functional residue map

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

Disulfide bonds (3): 498–508, 502–521, 523–532

Glycosylation sites (3): 144, 407, 431

Mutagenesis-validated functional residues (5):

Position	Phenotype
584	no effect.
588	abolishes shedding of cripto.
610	abolishes shedding of cripto.
722	abolishes shedding of cripto.
726	abolishes shedding of cripto.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GOCC_VACUOLAR_MEMBRANE, GOZGIT_ESR1_TARGETS_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_LIPID_METABOLIC_PROCESS, NIKOLSKY_BREAST_CANCER_16P13_AMPLICON, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_CARBOXYLIC_ESTER_HYDROLASE_ACTIVITY, GOMF_PHOSPHOLIPASE_A2_ACTIVITY, GOMF_LIPASE_ACTIVITY, SENESE_HDAC1_AND_HDAC2_TARGETS_UP, GOMF_PHOSPHOLIPASE_ACTIVITY, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, WANG_METASTASIS_OF_BREAST_CANCER_ESR1_UP, MARTENS_TRETINOIN_RESPONSE_UP, CHYLA_CBFA2T3_TARGETS_DN

GO Biological Process (1): lipid metabolic process (GO:0006629)

GO Molecular Function (3): A2-type glycerophospholipase activity (GO:0004623), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), lysosome (GO:0005764), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
glycerophospholipase activity	1
carboxylic ester hydrolase activity	1
binding	1
catalytic activity	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
extracellular vesicle	1
lytic vacuole	1
cellular anatomical structure	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGAP6	NPRL3	Q12980	582
PGAP6	ACER1	Q8TDN7	540
PGAP6	PGAP3	Q96FM1	513
PGAP6	ACER2	Q5QJU3	489
PGAP6	TTC21A	Q8NDW8	479
PGAP6	PGAP2	Q9UHJ9	474
PGAP6	PGAP1	Q75T13	472
PGAP6	TIMM17B	O60830	458
PGAP6	ANKRD27	Q96NW4	456
PGAP6	IGDCC4	Q8TDY8	454
PGAP6	SIDT1	Q9NXL6	448
PGAP6	PIGB	Q92521	412
PGAP6	HMGXB4	Q9UGU5	410
PGAP6	LUC7L	Q9NQ29	408
PGAP6	PIGK	Q92643	393

IntAct

65 interactions, top by confidence:

A	B	Type	Score
KRTAP10-7	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
REL	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
PGAP6		psi-mi:“MI:0915”(physical association)	0.560
PGAP6	CYSRT1	psi-mi:“MI:0915”(physical association)	0.560
PGAP6	KRTAP6-3	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLC	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-1	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
KRT31	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-3	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
HNRNPK	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	PGAP6	psi-mi:“MI:0915”(physical association)	0.560
SPPL2B	UQCRQ	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMPRSS11B		psi-mi:“MI:0914”(association)	0.350
ASIC4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
ATP1B4	RTN2	psi-mi:“MI:0914”(association)	0.350
rep	B4GALT3	psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): TMEM8A (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-3 (Two-hybrid), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), TMEM8A (Two-hybrid), REL (Two-hybrid), HNRNPK (Two-hybrid), KRTAP10-8 (Two-hybrid)

ESM2 similar proteins: A1L134, A9ULG4, B1H1N7, B2RUP2, D3ZI76, D3ZUM2, F1MLB4, I3L5V6, O95870, P47823, P70295, Q13144, Q14DK4, Q16586, Q1HAQ0, Q1JPD2, Q1LWG4, Q27J81, Q2TBP5, Q3TFD2, Q4R8P0, Q5NVK5, Q5R6S0, Q64350, Q643R3, Q6MG55, Q6NUI2, Q6NVG1, Q6PBN5, Q6PDS3, Q6SZW1, Q6V7V2, Q70J99, Q7TN37, Q8CHW4, Q8N0W3, Q8N9W5, Q8NF37, Q8TE02, Q95K25

Diamond homologs: A6NDV4, A6NI61, A6QLK4, B1AWJ5, Q6IQ69, Q9D1N4, Q9ESN3, Q9HCN3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 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
Keratinization	7	13.4×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	202
Likely benign	19
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2204 predictions. Top by Δscore:

Variant	Effect	Δscore
16:372282:GCC:G	acceptor_loss	1.0000
16:372283:CCTGG:C	acceptor_loss	1.0000
16:372284:C:CC	acceptor_gain	1.0000
16:372284:CTGG:C	acceptor_loss	1.0000
16:372610:CCCA:C	donor_gain	1.0000
16:372731:C:CT	acceptor_gain	1.0000
16:374002:CACG:C	donor_loss	1.0000
16:374003:A:AC	donor_gain	1.0000
16:374003:A:C	donor_loss	1.0000
16:374004:C:CA	donor_gain	1.0000
16:374004:CG:C	donor_gain	1.0000
16:374004:CGT:C	donor_gain	1.0000
16:374004:CGTA:C	donor_gain	1.0000
16:374004:CGTAT:C	donor_gain	1.0000
16:374007:A:AC	donor_gain	1.0000
16:374152:C:CC	acceptor_gain	1.0000
16:374299:C:CT	acceptor_gain	1.0000
16:374395:CCAGC:C	acceptor_gain	1.0000
16:374396:CAGCC:C	acceptor_gain	1.0000
16:374751:CTCA:C	donor_loss	1.0000
16:374752:TCA:T	donor_loss	1.0000
16:374753:CA:C	donor_loss	1.0000
16:374755:C:G	donor_loss	1.0000
16:374755:CCTG:C	donor_gain	1.0000
16:374892:CCTT:C	acceptor_gain	1.0000
16:374962:CAGG:C	acceptor_gain	1.0000
16:375131:A:AC	donor_gain	1.0000
16:375132:C:CC	donor_gain	1.0000
16:375132:CT:C	donor_gain	1.0000
16:375132:CTCAG:C	donor_gain	1.0000

AlphaMissense

4981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:372134:G:C	S723R	0.999
16:372134:G:T	S723R	0.999
16:372136:T:G	S723R	0.999
16:374314:G:C	S554R	0.999
16:374314:G:T	S554R	0.999
16:374316:T:G	S554R	0.999
16:374078:T:A	D610V	0.998
16:374315:C:A	S554I	0.997
16:374381:C:G	C532S	0.997
16:374382:A:T	C532S	0.997
16:374078:T:G	D610A	0.996
16:374138:C:T	C590Y	0.996
16:374311:G:C	N555K	0.996
16:374311:G:T	N555K	0.996
16:374052:A:G	W619R	0.995
16:374052:A:T	W619R	0.995
16:374078:T:C	D610G	0.995
16:374380:G:C	C532W	0.995
16:374381:C:T	C532Y	0.995
16:374764:C:G	C523S	0.995
16:374765:A:T	C523S	0.995
16:377415:G:T	A157D	0.995
16:372107:G:C	S732R	0.994
16:372107:G:T	S732R	0.994
16:372109:T:G	S732R	0.994
16:374070:C:G	G613R	0.994
16:374111:C:G	C599S	0.994
16:374112:A:T	C599S	0.994
16:374382:A:G	C532R	0.994
16:374386:C:A	W530C	0.994

dbSNP variants (sampled 300 via entrez): RS1000029973 (16:380988 G>T), RS1000215874 (16:377320 G>A), RS1000226676 (16:385944 C>A), RS1000242285 (16:380240 G>A), RS1000378942 (16:385154 A>G), RS1000661262 (16:384303 G>A), RS1000729044 (16:385440 T>C), RS1000813192 (16:388838 C>T), RS1000817892 (16:376614 C>A,T), RS1000827916 (16:385785 C>T), RS1001168499 (16:381741 G>C), RS1001332946 (16:373569 C>A,T), RS1001989608 (16:379755 C>G), RS1001999839 (16:385025 G>C,T), RS1002183000 (16:370728 G>C)

Disease associations

OMIM: gene MIM:619342 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST005364_1	Opioid requirements during laparoscopic-assisted colectomy	3.000000e-08
GCST005951_12	Body mass index	5.000000e-11
GCST010002_107	Refractive error	6.000000e-18
GCST90002390_642	Mean corpuscular hemoglobin	4.000000e-26
GCST90002391_70	Mean corpuscular hemoglobin concentration	9.000000e-16
GCST90002392_487	Mean corpuscular volume	5.000000e-22
GCST90002403_662	Red blood cell count	7.000000e-09
GCST90013407_140	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-23

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008541	response to opioid
EFO:0008544	analgesia requirement measurement
EFO:0004340	body mass index
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs199670311	PGAP6		0.00	0

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	4
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
clothianidin	decreases expression	1
(+)-JQ1 compound	increases expression	1
MT19c compound	decreases expression	1
Temozolomide	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	increases expression	1
Manganese	decreases expression, increases abundance	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases methylation	1
Okadaic Acid	increases expression	1
Vitamin K 3	affects expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5L5	HAP1 TMEM8A (-) 2	Cancer cell line	Male
CVCL_XU54	HAP1 TMEM8A (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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