PITHD1

Summary

PITHD1 (PITH domain containing 1, HGNC:25022) is a protein-coding gene on chromosome 1p36.11, encoding PITH domain-containing protein 1 (Q9GZP4). Promotes megakaryocyte differentiation by up-regulating RUNX1 expression.

Involved in positive regulation of DNA-templated transcription and positive regulation of megakaryocyte differentiation. Located in cytoplasm.

Source: NCBI Gene 57095 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 18 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_020362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25022
Approved symbol	PITHD1
Name	PITH domain containing 1
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	HT014, TXNL1CL
Ensembl gene	ENSG00000057757
Ensembl biotype	protein_coding
OMIM	618784
Entrez	57095

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000246151, ENST00000374524, ENST00000415372, ENST00000873427

RefSeq mRNA: 1 — MANE Select: NM_020362 NM_020362

CCDS: CCDS240

Canonical transcript exons

ENST00000246151 — 6 exons

Exon	Start	End
ENSE00000388676	23786315	23786423
ENSE00000758345	23779864	23779941
ENSE00000758346	23779438	23779481
ENSE00000859774	23778418	23778713
ENSE00001463736	23787275	23788232
ENSE00003650562	23785675	23785779

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.7324 / max 1220.8880, expressed in 1825 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1364	49.7324	1825

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.50	gold quality
oocyte	CL:0000023	99.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.28	gold quality
prefrontal cortex	UBERON:0000451	98.22	gold quality
hypothalamus	UBERON:0001898	98.18	gold quality
pons	UBERON:0000988	97.95	gold quality
cerebellar hemisphere	UBERON:0002245	97.90	gold quality
substantia nigra pars compacta	UBERON:0001965	97.89	gold quality
upper arm skin	UBERON:0004263	97.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.85	gold quality
anterior cingulate cortex	UBERON:0009835	97.85	gold quality
cerebellar cortex	UBERON:0002129	97.84	gold quality
right frontal lobe	UBERON:0002810	97.81	gold quality
superior vestibular nucleus	UBERON:0007227	97.72	gold quality
cerebellum	UBERON:0002037	97.70	gold quality
frontal cortex	UBERON:0001870	97.64	gold quality
frontal lobe	UBERON:0016525	97.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.63	gold quality
dorsal root ganglion	UBERON:0000044	97.61	gold quality
substantia nigra	UBERON:0002038	97.53	gold quality
neocortex	UBERON:0001950	97.50	gold quality
oviduct epithelium	UBERON:0004804	97.50	gold quality
midbrain	UBERON:0001891	97.44	gold quality
thymus	UBERON:0002370	97.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.41	gold quality
nucleus accumbens	UBERON:0001882	97.40	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.39	gold quality
amygdala	UBERON:0001876	97.38	gold quality
spinal cord	UBERON:0002240	97.28	gold quality
esophagus squamous epithelium	UBERON:0006920	97.24	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	14.23
E-HCAD-10	no	1.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting PITHD1, 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-3064-3P	100.00	70.09	1254
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-4799-3P	97.78	65.97	893
HSA-MIR-5699-5P	97.36	67.03	1014

Literature-anchored findings (GeneRIF, showing 3)

• PITHD1 was a novel activator of IRES and enhanced RUNX1 expression that subsequently promoted megakaryocyte differentiation. (PMID:25134913)
• An association of lower PITHD1 protein expression and unfavorable overall and disease-specific survival in clear-cell ovarian carcinoma patients (PMID:31533654)
• Combination of Antibody Arrays to Functionally Characterize Dark Proteins in Human Olfactory Neuroepithelial Cells. (PMID:34115363)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pithd1	ENSDARG00000098600
mus_musculus	Pithd1	ENSMUSG00000028669
rattus_norvegicus	Pithd1	ENSRNOG00000010873
drosophila_melanogaster	CG6153	FBGN0032445
caenorhabditis_elegans		WBGENE00022704

Protein

Protein identifiers

PITH domain-containing protein 1 — Q9GZP4 (reviewed: Q9GZP4)

All UniProt accessions (3): Q9GZP4, X6R8S9, X6RHB9

UniProt curated annotations — full annotation on UniProt →

Function. Promotes megakaryocyte differentiation by up-regulating RUNX1 expression. Regulates RUNX1 expression by activating the proximal promoter of the RUNX1 gene and by enhancing the translation activity of an internal ribosome entry site (IRES) element in the RUNX1 gene.

Subcellular location. Cytoplasm.

Tissue specificity. Down-regulated in primary acute myeloid leukemia (AML) patients.

Induction. Up-regulated in K562 and HEL cells undergoing megakaryocyte differentiation induced by phorbol myristate acetate (PMA).

Similarity. Belongs to the PITHD1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZP4-1	1	yes
Q9GZP4-2	2

RefSeq proteins (1): NP_065095* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR010400	PITH_dom	Domain
IPR037047	PITH_dom_sf	Homologous_superfamily
IPR045099	PITH1-like	Family

Pfam: PF06201

UniProt features (4 total): chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZP4-F1	84.35	0.70

Functional residue map

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

Post-translational modifications (1): 189

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 157 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SINGLE_FERTILIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_MEGAKARYOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_POSITIVE_REGULATION_OF_MYELOID_CELL_DIFFERENTIATION, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, GOBP_MEGAKARYOCYTE_DIFFERENTIATION

GO Biological Process (8): spermatid development (GO:0007286), penetration of zona pellucida (GO:0007341), positive regulation of megakaryocyte differentiation (GO:0045654), positive regulation of DNA-templated transcription (GO:0045893), regulation of proteasomal protein catabolic process (GO:0061136), penetration of cumulus oophorus (GO:0061956), regulation of macromolecule metabolic process (GO:0060255), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (0):

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), sperm cytoplasmic droplet (GO:0097598)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
single fertilization	2
multicellular organismal reproductive process	2
regulation of metabolic process	2
germ cell development	1
spermatid differentiation	1
multi-multicellular organism process	1
megakaryocyte differentiation	1
positive regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
macromolecule metabolic process	1
primary metabolic process	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PITHD1	MATCAP1	Q68EN5	474
PITHD1	NECAP2	Q9NVZ3	413
PITHD1	EXOC3L1	Q86VI1	394
PITHD1	FUCA1	P04066	389
PITHD1	TARM1	B6A8C7	374
PITHD1	NSF	P46459	374
PITHD1	LYPLA2	O95372	372
PITHD1	B3GNT9	Q6UX72	371
PITHD1	FRMPD2	Q68DX3	370
PITHD1	Q8WV35	Q8WV35	367
PITHD1	DXO	O77932	360
PITHD1	GPR158	Q5T848	356
PITHD1	PPA1	Q15181	353
PITHD1	KIF26B	Q2KJY2	349
PITHD1	TMEM208	Q9BTX3	349

IntAct

25 interactions, top by confidence:

A	B	Type	Score
FNTB	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PITHD1	EEF1A2	psi-mi:“MI:0914”(association)	0.530
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
PITHD1	RECQL5	psi-mi:“MI:0914”(association)	0.350
FXR2	RPS21	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
METTL9	SLC27A2	psi-mi:“MI:0914”(association)	0.350
ZDHHC19	QSOX1	psi-mi:“MI:0914”(association)	0.350
WDR59	HDAC3	psi-mi:“MI:0914”(association)	0.350
RRM2	CREB1	psi-mi:“MI:0914”(association)	0.350
PITHD1	FRA10AC1	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
FNTA	CHURC1-FNTB	psi-mi:“MI:0914”(association)	0.350
METTL9	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
HUNK	PITHD1	psi-mi:“MI:0915”(physical association)	0.000
PITHD1	CDC73	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (52): PITHD1 (Affinity Capture-MS), PITHD1 (Affinity Capture-MS), PITHD1 (Affinity Capture-MS), PITHD1 (Affinity Capture-MS), CETN2 (Co-fractionation), PITHD1 (Co-fractionation), PITHD1 (Co-fractionation), PITHD1 (Co-fractionation), SLK (Co-fractionation), YWHAB (Co-fractionation), PITHD1 (Affinity Capture-MS), WDR59 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), EEF1A2 (Affinity Capture-MS), PITHD1 (Affinity Capture-MS)

ESM2 similar proteins: A2VE21, G3GTP0, O02485, O43396, O43747, O81742, P09874, P11103, P18493, P22892, P26446, P27008, P31669, P49917, P53620, Q29L80, Q4AEF8, Q4HYB8, Q58DV0, Q5R5M2, Q5RCE3, Q5RHR0, Q5ZK01, Q66JI9, Q6DJI5, Q6DKD7, Q6NYX8, Q8BTF7, Q8BWR2, Q8CDN6, Q8X0X6, Q90YB1, Q920B9, Q920J4, Q95ZI6, Q9BRX2, Q9GZP4, Q9I8E6, Q9PUE4, Q9QXK3

Diamond homologs: A2YIW7, C9K7C5, G4NFB7, O14463, O43396, O48897, O64394, O65049, O97508, O97680, P07591, P08628, P08629, P10599, P10639, P11232, P22217, P29429, P29445, P29446, P29447, P29450, P29451, P34723, P42115, P50413, P80028, P82460, P85801, Q0D840, Q0DKF1, Q1RQI9, Q1RQJ0, Q1RQJ1, Q29L80, Q54KN7, Q5R9M3, Q5UR29, Q5WNE3, Q5XHX6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

657 predictions. Top by Δscore:

Variant	Effect	Δscore
1:23778710:CAAGG:C	donor_loss	1.0000
1:23778712:AGGT:A	donor_loss	1.0000
1:23778714:GT:G	donor_loss	1.0000
1:23779938:GACT:G	donor_gain	1.0000
1:23779942:G:GG	donor_gain	1.0000
1:23785670:CTCA:C	acceptor_loss	1.0000
1:23785672:CA:C	acceptor_loss	1.0000
1:23785673:A:AG	acceptor_gain	1.0000
1:23785673:A:AT	acceptor_loss	1.0000
1:23785674:G:GC	acceptor_loss	1.0000
1:23785674:G:GG	acceptor_gain	1.0000
1:23785768:G:GG	donor_gain	1.0000
1:23785776:CAAA:C	donor_gain	1.0000
1:23785778:AA:A	donor_gain	1.0000
1:23785778:AAG:A	donor_loss	1.0000
1:23785779:AGTAA:A	donor_loss	1.0000
1:23785780:G:GG	donor_gain	1.0000
1:23785781:T:A	donor_loss	1.0000
1:23787269:TTGCA:T	acceptor_loss	1.0000
1:23787270:TGCAG:T	acceptor_loss	1.0000
1:23787271:GCAGC:G	acceptor_loss	1.0000
1:23787272:CAGCT:C	acceptor_loss	1.0000
1:23787273:A:AG	acceptor_gain	1.0000
1:23787273:A:G	acceptor_loss	1.0000
1:23787274:G:A	acceptor_loss	1.0000
1:23787274:G:GG	acceptor_gain	1.0000
1:23779436:A:AG	acceptor_gain	0.9900
1:23779437:G:GG	acceptor_gain	0.9900
1:23785673:AG:A	acceptor_gain	0.9900
1:23785674:GG:G	acceptor_gain	0.9900

AlphaMissense

1390 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:23779442:T:A	V68D	0.998
1:23779466:T:C	L76P	0.998
1:23779472:T:C	F78S	0.998
1:23779878:T:A	V86D	0.998
1:23779884:T:A	L88H	0.998
1:23785700:T:C	F116L	0.998
1:23785702:T:A	F116L	0.998
1:23785702:T:G	F116L	0.998
1:23778641:C:G	C42W	0.997
1:23779447:A:C	S70R	0.997
1:23779449:T:A	S70R	0.997
1:23779449:T:G	S70R	0.997
1:23779866:T:C	F82S	0.997
1:23786344:T:A	L152H	0.997
1:23786344:T:C	L152P	0.997
1:23779469:T:C	L77P	0.996
1:23779926:C:A	P102H	0.996
1:23786409:G:A	G174R	0.996
1:23786409:G:C	G174R	0.996
1:23786410:G:A	G174E	0.996
1:23778679:T:C	F55S	0.995
1:23779466:T:A	L76H	0.995
1:23785684:T:A	N110K	0.995
1:23785684:T:G	N110K	0.995
1:23786326:T:C	F146S	0.995
1:23778643:T:C	L43P	0.994
1:23779884:T:G	L88R	0.994
1:23779941:T:C	L107P	0.994
1:23786325:T:C	F146L	0.994
1:23786327:T:A	F146L	0.994

dbSNP variants (sampled 300 via entrez): RS1000108231 (1:23781807 A>C), RS1000337744 (1:23781235 G>A), RS1000405384 (1:23786906 A>G), RS1000498460 (1:23788339 AT>A), RS1000565832 (1:23786979 A>G), RS1000930645 (1:23776443 G>C), RS1001186040 (1:23788622 A>G), RS1001261443 (1:23776728 C>T), RS1001352881 (1:23779860 G>A), RS1001385343 (1:23780107 T>A,C), RS1001731007 (1:23779816 A>C,G,T), RS1001778568 (1:23780189 C>G,T), RS1002356512 (1:23785022 T>C), RS1002500841 (1:23788608 C>G,T), RS1003403412 (1:23778278 A>C,G,T)

Disease associations

OMIM: gene MIM:618784 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004612_195	High light scatter reticulocyte percentage of red cells	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725173 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178899: Inhibition of C1ORF128 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, increases methylation	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases 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	increases expression, affects cotreatment	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Coal	increases abundance, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Lead	affects splicing, affects expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Quercetin	increases expression	1
Silver	increases expression	1
Smoke	decreases expression, increases abundance	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697629	Binding	Inhibition of C1ORF128 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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