PFAS

Summary

PFAS (phosphoribosylformylglycinamidine synthase, HGNC:8863) is a protein-coding gene on chromosome 17p13.1, encoding Phosphoribosylformylglycinamidine synthase (O15067). Phosphoribosylformylglycinamidine synthase involved in the purines biosynthetic pathway. It is a selective cancer dependency (DepMap: 34.6% of cell lines).

Purines are necessary for many cellular processes, including DNA replication, transcription, and energy metabolism. Ten enzymatic steps are required to synthesize inosine monophosphate (IMP) in the de novo pathway of purine biosynthesis. The enzyme encoded by this gene catalyzes the fourth step of IMP biosynthesis.

Source: NCBI Gene 5198 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 248 total — 2 pathogenic, 2 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 34.6% of screened cell lines
• MANE Select transcript: NM_012393

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8863
Approved symbol	PFAS
Name	phosphoribosylformylglycinamidine synthase
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	PURL, FGARAT, KIAA0361, GATD8
Ensembl gene	ENSG00000178921
Ensembl biotype	protein_coding
OMIM	602133
Entrez	5198

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000314666, ENST00000546020, ENST00000578979, ENST00000580251, ENST00000580356, ENST00000581242, ENST00000581288, ENST00000583059, ENST00000584044, ENST00000585183, ENST00000585319, ENST00000625942, ENST00000897613, ENST00000937382, ENST00000937383, ENST00000937384, ENST00000937385, ENST00000937386, ENST00000937387, ENST00000937388, ENST00000937389, ENST00000955445

RefSeq mRNA: 1 — MANE Select: NM_012393 NM_012393

CCDS: CCDS11136

Canonical transcript exons

ENST00000314666 — 28 exons

Exon	Start	End
ENSE00001233777	8256524	8256648
ENSE00001233786	8256267	8256407
ENSE00001233803	8255502	8255691
ENSE00002686732	8268954	8270486
ENSE00003458639	8265288	8265468
ENSE00003471018	8268533	8268856
ENSE00003477524	8255027	8255132
ENSE00003515511	8258071	8258199
ENSE00003528927	8262920	8262993
ENSE00003536810	8263775	8263936
ENSE00003555219	8253859	8254079
ENSE00003565998	8264212	8264337
ENSE00003566414	8257807	8257938
ENSE00003573098	8263575	8263636
ENSE00003595205	8265862	8266017
ENSE00003599795	8263109	8263265
ENSE00003605761	8265556	8265639
ENSE00003608235	8255805	8255910
ENSE00003611867	8267372	8267463
ENSE00003619125	8266234	8266353
ENSE00003619462	8256835	8256963
ENSE00003628698	8266753	8266898
ENSE00003649078	8254166	8254301
ENSE00003653517	8264470	8264601
ENSE00003657732	8267028	8267235
ENSE00003664456	8267551	8267665
ENSE00003675038	8264895	8265125
ENSE00003845264	8249289	8249339

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 88.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3914 / max 192.9216, expressed in 1779 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159477	24.9354	1763
159475	0.4454	203
159478	0.0106	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	88.60	gold quality
embryo	UBERON:0000922	88.28	gold quality
ganglionic eminence	UBERON:0004023	87.41	gold quality
cortical plate	UBERON:0005343	85.72	gold quality
colonic epithelium	UBERON:0000397	84.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.80	gold quality
right ovary	UBERON:0002118	83.78	gold quality
right adrenal gland	UBERON:0001233	83.73	gold quality
right lobe of thyroid gland	UBERON:0001119	83.62	gold quality
left ovary	UBERON:0002119	83.41	gold quality
left adrenal gland cortex	UBERON:0035825	83.21	gold quality
metanephros cortex	UBERON:0010533	83.20	gold quality
left adrenal gland	UBERON:0001234	83.12	gold quality
ovary	UBERON:0000992	83.01	gold quality
right adrenal gland cortex	UBERON:0035827	82.93	gold quality
left uterine tube	UBERON:0001303	82.66	gold quality
adrenal gland	UBERON:0002369	82.60	gold quality
granulocyte	CL:0000094	82.45	gold quality
right lobe of liver	UBERON:0001114	82.45	gold quality
body of pancreas	UBERON:0001150	82.39	gold quality
stromal cell of endometrium	CL:0002255	82.35	gold quality
vermiform appendix	UBERON:0001154	82.34	gold quality
body of uterus	UBERON:0009853	82.34	gold quality
bone marrow cell	CL:0002092	82.27	gold quality
body of stomach	UBERON:0001161	82.26	gold quality
spleen	UBERON:0002106	82.24	gold quality
rectum	UBERON:0001052	81.92	gold quality
adrenal cortex	UBERON:0001235	81.85	gold quality
mucosa of transverse colon	UBERON:0004991	81.81	gold quality
left lobe of thyroid gland	UBERON:0001120	81.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

49 targeting PFAS, 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-4455	100.00	65.48	1587
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-423-5P	98.69	67.48	1522

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• Study observed FGAMS as distinct puncta throughout neuronal processes, where it co-localized with neurofilament heavy chain, tubulin, and mitochondria. Data provide insight into potential purine biosynthetic mechanisms utilized within neurons during homeostasis as well as viral infection. (PMID:29337348)
• A total of 429 proteins are newly identified to interact with PFAS. PFAS interacts with CAD, CCT2, PRDX1, and PHGDH. (PMID:30987822)
• ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis. (PMID:32485148)
• NSUN2-mediated m[5] C RNA methylation dictates retinoblastoma progression through promoting PFAS mRNA stability and expression. (PMID:37228185)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pfas	ENSDARG00000003750
mus_musculus	Pfas	ENSMUSG00000020899
rattus_norvegicus	Pfas	ENSRNOG00000005193
drosophila_melanogaster	Pfas	FBGN0000052
caenorhabditis_elegans		WBGENE00008654

Protein

Protein identifiers

Phosphoribosylformylglycinamidine synthase — O15067 (reviewed: O15067)

Alternative names: Formylglycinamide ribonucleotide amidotransferase, Formylglycinamide ribotide amidotransferase, Phosphoribosylformylglycineamide amidotransferase

All UniProt accessions (8): O15067, H0YGH1, J3KT98, J3KTL4, J3KTQ5, J3QL39, J3QSG0, J3QSH6

UniProt curated annotations — full annotation on UniProt →

Function. Phosphoribosylformylglycinamidine synthase involved in the purines biosynthetic pathway. Catalyzes the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to yield formylglycinamidine ribonucleotide (FGAM) and glutamate.

Subcellular location. Cytoplasm.

Pathway. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole from N(2)-formyl-N(1)-(5-phospho-D-ribosyl)glycinamide: step 1/2.

Similarity. In the N-terminal section; belongs to the FGAMS family.

RefSeq proteins (1): NP_036525* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010073	PurL_large	Family
IPR010918	PurM-like_C_dom	Domain
IPR029062	Class_I_gatase-like	Homologous_superfamily
IPR036604	PurS-like_sf	Homologous_superfamily
IPR036676	PurM-like_C_sf	Homologous_superfamily
IPR036921	PurM-like_N_sf	Homologous_superfamily
IPR040707	FGAR-AT_N	Domain
IPR041609	PurL_linker	Domain
IPR055181	FGAR-AT_PurM_N-like	Domain

Pfam: PF02769, PF13507, PF18072, PF18076, PF22689

Enzyme classification (BRENDA):

• EC 6.3.5.3 — phosphoribosylformylglycinamidine synthase (BRENDA: 17 organisms, 17 substrates, 19 inhibitors, 20 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.181–1.5	4
5’-PHOSPHORIBOSYLFORMYLGLYCINAMIDE	0.06–0.1	2
GLN	0.11–0.2	2
L-GLN	0.03	2
NH4+	1–7.5	2
(-)CARBOCYCLIC-5’-PHOSPHORIBOSYLFORMYLGLYCINAMID	0.0468	1
BETA-5’-PHOSPHORIBOSYLFORMYLGLYCINAMIDE	0.23	1
FORMYLGLYCINAMIDE RIBONUCLEOTIDE	0.507	1
L-GLUTAMINE	1.3	1
N2-FORMYL-N1-(5-PHOSPHO-D-RIBOSYL)GLYCINAMIDE	0.18	1

Catalyzed reactions (Rhea), 1 shown:

• N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide + L-glutamine + ATP + H2O = 2-formamido-N(1)-(5-O-phospho-beta-D-ribosyl)acetamidine + L-glutamate + ADP + phosphate + H(+) (RHEA:17129)

UniProt features (22 total): binding site 8, modified residue 4, sequence variant 4, active site 3, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9NB3	ELECTRON MICROSCOPY	3.19
9NAL	ELECTRON MICROSCOPY	3.22
9N9W	ELECTRON MICROSCOPY	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15067-F1	92.52	0.84

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 (3): 1158 (nucleophile); 1297; 1299

Ligand- & substrate-binding residues (8): 750; 909; 911; 322–333; 402–404; 706; 707; 746

Post-translational modifications (4): 215, 569, 619, 623

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis

MSigDB gene sets: 211 (showing top): ATF_B, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUTAMINE_METABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, CREB_Q4, ATF1_Q6, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GNF2_RFC3, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP

GO Biological Process (9): purine nucleotide biosynthetic process (GO:0006164), GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), L-glutamine metabolic process (GO:0006541), purine ribonucleoside monophosphate biosynthetic process (GO:0009168), response to xenobiotic stimulus (GO:0009410), ‘de novo’ AMP biosynthetic process (GO:0044208), anterior head development (GO:0097065), ‘de novo’ XMP biosynthetic process (GO:0097294)

GO Molecular Function (5): phosphoribosylformylglycinamidine synthase activity (GO:0004642), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine-containing compound biosynthetic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
GMP metabolic process	1
IMP biosynthetic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
purine nucleoside monophosphate biosynthetic process	1
ribonucleoside monophosphate biosynthetic process	1
purine ribonucleoside monophosphate metabolic process	1
response to chemical	1
AMP biosynthetic process	1
head development	1
XMP biosynthetic process	1
carbon-nitrogen ligase activity, with glutamine as amido-N-donor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFAS	PPAT	Q06203	983
PFAS	GART	P22102	977
PFAS	REEP5	Q00765	918
PFAS	ADSL	P30566	801
PFAS	ATIC	P31939	791
PFAS	PAICS	P22234	762
PFAS	POLR2B	P30876	667
PFAS	CTPS1	P17812	635
PFAS	GMPS	P49915	617
PFAS	LINS1	Q8NG48	542
PFAS	CAD	P27708	508
PFAS	HAAO	P46952	506
PFAS	IMPDH2	P12268	495
PFAS	ADSS2	P30520	489
PFAS	RIGI	O95786	458

IntAct

64 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Bag2		psi-mi:“MI:0914”(association)	0.350
DNAJC7	HSPA8	psi-mi:“MI:0914”(association)	0.350
DUX4		psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
	NDUFAF8	psi-mi:“MI:0914”(association)	0.350
KEAP1	VWA8	psi-mi:“MI:0914”(association)	0.350
UIMC1	PYCR3	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
PRKAG2	PFAS	psi-mi:“MI:0914”(association)	0.350
NIPSNAP2	PFAS	psi-mi:“MI:0914”(association)	0.350
RMC1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
RMC1	ARID1A	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
GTF3C4	PFAS	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	UBA6	psi-mi:“MI:0914”(association)	0.350
DND1	UBA6	psi-mi:“MI:0914”(association)	0.350
ERF	DVL2	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (205): PFAS (Affinity Capture-RNA), PFAS (Affinity Capture-RNA), PFAS (Affinity Capture-RNA), PFAS (Affinity Capture-MS), ADSL (Co-fractionation), EIF4H (Co-fractionation), PABPC1 (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation), PFAS (Co-fractionation)

ESM2 similar proteins: A0LIN6, A1ANJ7, A1VD24, A1VF55, A2C7G2, A2CCB6, A5GIK5, A5GMV4, A5GW48, A5W7G2, B0KTX5, B1J5G5, B2GKK6, B5EQG3, B5FSZ0, B5XP95, B7JAG8, B8J025, C1D0A9, O14841, O15067, P27708, P97608, Q10093, Q10094, Q1I447, Q2JJA1, Q2JKQ8, Q2JLQ2, Q30WM4, Q30ZN1, Q39YF3, Q3AMW4, Q50899, Q5FNS3, Q5HZE4, Q5P5G2, Q72B00, Q72DJ9, Q75WB5

Diamond homologs: A0R8Z5, A4G010, A6VIG8, A9VRF0, B1YJ04, B7HS31, B7IUV2, B7JM84, B8DDY7, C3L531, C3PBM9, C5D4H9, O14228, O15067, O29008, P15254, P35421, P38972, P43847, P65904, P74881, P99166, Q085S1, Q0HKU9, Q0HX47, Q0I5H4, Q0TET1, Q12PR7, Q15R69, Q18FM4, Q19311, Q1C5E7, Q1CKD2, Q1D9V4, Q1H2I8, Q1R8H7, Q2FI10, Q2FZJ1, Q2NS22, Q2SK05

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	PFAS	phosphorylation
PFAS	“down-regulates quantity”	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	“chemical modification”
PFAS	“down-regulates quantity”	“L-glutamine zwitterion”	“chemical modification”
PFAS	“up-regulates quantity”	2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	“chemical modification”
PFAS	“up-regulates quantity”	“glutamic acid”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	188
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2202444	NM_025099.6(CTC1):c.1A>G (p.Met1Val)	Pathogenic
3767280	NM_012393.3(PFAS):c.681-1G>A	Pathogenic
3767279	NM_012393.3(PFAS):c.2431C>T (p.Arg811Trp)	Likely pathogenic
3770161	NM_012393.3(PFAS):c.792C>G (p.Asn264Lys)	Likely pathogenic

SpliceAI

3774 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8249340:G:GG	donor_gain	1.0000
17:8254161:T:TA	acceptor_gain	1.0000
17:8254161:TGCA:T	acceptor_loss	1.0000
17:8254163:CAGC:C	acceptor_loss	1.0000
17:8254164:A:AC	acceptor_loss	1.0000
17:8254164:A:AG	acceptor_gain	1.0000
17:8254164:AGCT:A	acceptor_gain	1.0000
17:8254164:AGCTG:A	acceptor_gain	1.0000
17:8254165:G:GG	acceptor_gain	1.0000
17:8254165:GC:G	acceptor_gain	1.0000
17:8254165:GCT:G	acceptor_gain	1.0000
17:8254165:GCTG:G	acceptor_gain	1.0000
17:8254165:GCTGA:G	acceptor_gain	1.0000
17:8254297:CCCAG:C	donor_gain	1.0000
17:8254298:CCAG:C	donor_gain	1.0000
17:8254299:CAG:C	donor_gain	1.0000
17:8254300:AG:A	donor_gain	1.0000
17:8254301:GG:G	donor_gain	1.0000
17:8254302:G:GG	donor_gain	1.0000
17:8254302:GTAA:G	donor_loss	1.0000
17:8255494:A:AG	acceptor_gain	1.0000
17:8255495:C:G	acceptor_gain	1.0000
17:8255500:A:AG	acceptor_gain	1.0000
17:8255500:AGTTT:A	acceptor_gain	1.0000
17:8255501:G:GC	acceptor_gain	1.0000
17:8255501:GT:G	acceptor_gain	1.0000
17:8255501:GTT:G	acceptor_gain	1.0000
17:8255501:GTTT:G	acceptor_gain	1.0000
17:8255501:GTTTG:G	acceptor_gain	1.0000
17:8255687:GCTTG:G	donor_gain	1.0000

AlphaMissense

8635 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8263245:A:C	D516A	1.000
17:8263245:A:T	D516V	1.000
17:8256274:A:C	S230R	0.999
17:8256276:C:A	S230R	0.999
17:8256276:C:G	S230R	0.999
17:8256402:C:A	N272K	0.999
17:8256402:C:G	N272K	0.999
17:8256638:C:A	N312K	0.999
17:8256638:C:G	N312K	0.999
17:8263246:T:A	D516E	0.999
17:8263246:T:G	D516E	0.999
17:8263250:G:C	G518R	0.999
17:8263579:T:A	N524K	0.999
17:8263579:T:G	N524K	0.999
17:8256273:C:A	H229Q	0.998
17:8256273:C:G	H229Q	0.998
17:8256391:T:C	F269L	0.998
17:8256393:C:A	F269L	0.998
17:8256393:C:G	F269L	0.998
17:8256403:A:C	S273R	0.998
17:8256405:C:A	S273R	0.998
17:8256405:C:G	S273R	0.998
17:8256633:C:G	H311D	0.998
17:8256886:A:C	D333A	0.998
17:8256886:A:T	D333V	0.998
17:8256887:T:A	D333E	0.998
17:8256887:T:G	D333E	0.998
17:8257887:A:C	S386R	0.998
17:8257889:T:A	S386R	0.998
17:8257889:T:G	S386R	0.998

dbSNP variants (sampled 300 via entrez): RS1000005296 (17:8261529 G>A), RS1000241243 (17:8247064 G>A,C), RS1000371072 (17:8270166 C>T), RS1000787486 (17:8249720 T>A,C), RS1000933237 (17:8261831 G>A,T), RS1001019300 (17:8251211 G>A,T), RS1001071195 (17:8251346 A>G), RS1001094257 (17:8245750 A>G), RS1001178402 (17:8248685 G>A,C), RS1001389083 (17:8256705 T>C), RS1001535669 (17:8258700 G>A), RS1001714998 (17:8251431 G>A), RS1001727047 (17:8267852 GTA>G,GTATA), RS1001874054 (17:8257487 C>T), RS1002025291 (17:8252252 C>T)

Disease associations

OMIM: gene MIM:602133 | disease phenotypes: MIM:127550, MIM:612199, MIM:105650

GenCC curated gene-disease

Mondo (4): dyskeratosis congenita (MONDO:0015780), cerebroretinal microangiopathy with calcifications and cysts 1 (MONDO:0024564), Diamond-Blackfan anemia (MONDO:0015253), retinal disorder (MONDO:0005283)

Orphanet (3): Dyskeratosis congenita (Orphanet:1775), Coats plus syndrome (Orphanet:313838), Diamond-Blackfan anemia (Orphanet:124)

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST003303_4	LDL cholesterol	1.000000e-08
GCST004139_15	Bipolar disorder	2.000000e-07
GCST004233_62	LDL cholesterol levels	1.000000e-07
GCST004601_143	Red blood cell count	5.000000e-11
GCST004604_29	Hematocrit	5.000000e-17
GCST004605_20	Mean corpuscular hemoglobin concentration	5.000000e-09
GCST004615_110	Hemoglobin concentration	1.000000e-10
GCST005023_29	Initial pursuit acceleration	9.000000e-06
GCST010083_329	Hemoglobin levels	1.000000e-12
GCST90002383_61	Hematocrit	3.000000e-11
GCST90002387_20	Immature fraction of reticulocytes	4.000000e-13
GCST90002391_89	Mean corpuscular hemoglobin concentration	1.000000e-18
GCST90002397_730	Mean spheric corpuscular volume	2.000000e-20
GCST90002403_348	Red blood cell count	3.000000e-20

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004509	hemoglobin measurement
EFO:0008434	initial pursuit acceleration

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D029503	Anemia, Diamond-Blackfan	C15.378.050.085.080.090; C15.378.050.750.500; C15.378.190.223.500.500.090; C16.320.077.090
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
D012164	Retinal Diseases	C11.768

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295655 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Cisplatin	decreases expression, affects expression	2
Valproic Acid	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
nickel chloride	decreases expression	1
ochratoxin A	affects cotreatment, increases expression	1
potassium chromate(VI)	increases expression	1
monobutyl phthalate	affects cotreatment, affects expression	1
2-ethyl-5-carboxypentyl phthalate	affects cotreatment, affects expression	1
mono(2-ethyl-5-oxohexyl)phthalate	affects cotreatment, affects expression	1
CGP 52608	affects binding, increases reaction	1
mono-benzyl phthalate	affects cotreatment, 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
mono(2-ethyl-5-hydroxyhexyl) phthalate	affects cotreatment, affects expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118608	Binding	Binding affinity to PFAS 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)

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

Trial	Phase	Status	Title
NCT00673608	PHASE4	COMPLETED	Magnetic Resonance Imaging (MRI) Assessments of the Heart and Liver Iron Load in Patients With Transfusion Induced Iron Overload
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT00001962	PHASE2	TERMINATED	A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
NCT00011505	PHASE2	COMPLETED	Mobilization of Stem Cells With G-CSF for Collection From Patients With Diamond-Blackfan Anemia
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00957931	PHASE2	COMPLETED	Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT02386267	PHASE2	UNKNOWN	L-leucine in Diamond Blackfan Anemia Patients
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04099966	PHASE2	RECRUITING	AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01362595	PHASE1/PHASE2	COMPLETED	Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT01464164	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Study of Sotatercept in Adults With Transfusion Dependent Diamond Blackfan Anemia