PHF5A

Summary

PHF5A (PHD finger protein 5A, HGNC:18000) is a protein-coding gene on chromosome 22q13.2, encoding PHD finger-like domain-containing protein 5A (Q7RTV0). Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes a subunit of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron’s branch site in a sequence-independent manner and may anchor the U2 snRNP to the pre-mRNA. The protein encoded by this gene contains a PHD-finger-like domain that is flanked by highly basic N- and C-termini. This protein belongs to the PHD-finger superfamily and may act as a chromatin-associated protein. This gene has several pseudogenes on different chromosomes.

Source: NCBI Gene 84844 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 15 total — 2 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_032758

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18000
Approved symbol	PHF5A
Name	PHD finger protein 5A
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC1346, SF3b14b, INI, bK223H9.2, Rds3, SAP14b, SF3B7
Ensembl gene	ENSG00000100410
Ensembl biotype	protein_coding
OMIM	617846
Entrez	84844

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000216252, ENST00000459687, ENST00000491254, ENST00000899733, ENST00000899734, ENST00000913766

RefSeq mRNA: 1 — MANE Select: NM_032758 NM_032758

CCDS: CCDS14016

Canonical transcript exons

ENST00000216252 — 4 exons

Exon	Start	End
ENSE00001176238	41468602	41468692
ENSE00001202354	41459717	41460487
ENSE00003625067	41468124	41468147
ENSE00003625309	41467448	41467614

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.3120 / max 689.6874, expressed in 1815 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194363	44.3120	1815

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.92	gold quality
secondary oocyte	CL:0000655	95.01	gold quality
ileal mucosa	UBERON:0000331	94.17	gold quality
mucosa of transverse colon	UBERON:0004991	93.13	gold quality
monocyte	CL:0000576	93.09	gold quality
leukocyte	CL:0000738	93.09	gold quality
calcaneal tendon	UBERON:0003701	92.77	gold quality
islet of Langerhans	UBERON:0000006	92.65	gold quality
ventricular zone	UBERON:0003053	92.60	gold quality
tibialis anterior	UBERON:0001385	92.48	gold quality
ganglionic eminence	UBERON:0004023	92.13	gold quality
cortical plate	UBERON:0005343	91.70	gold quality
granulocyte	CL:0000094	91.55	gold quality
rectum	UBERON:0001052	91.36	gold quality
upper arm skin	UBERON:0004263	91.20	gold quality
gastrocnemius	UBERON:0001388	91.18	gold quality
muscle of leg	UBERON:0001383	91.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.01	gold quality
stromal cell of endometrium	CL:0002255	90.82	gold quality
pancreas	UBERON:0001264	90.59	gold quality
body of stomach	UBERON:0001161	90.55	gold quality
lymph node	UBERON:0000029	90.39	gold quality
bone marrow	UBERON:0002371	90.28	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.22	gold quality
body of pancreas	UBERON:0001150	90.21	gold quality
skin of abdomen	UBERON:0001416	90.01	gold quality
esophagus mucosa	UBERON:0002469	89.97	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.94	gold quality
esophagus	UBERON:0001043	89.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CD79A
CSF1
GJA1
IGHE
MYH6
SMARCB1

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

44 targeting PHF5A, 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-3162-3P	100.00	65.37	363
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-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4326	98.97	67.63	962

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• The molecular and genetic research in this paper is performed on mouse but the paper identifies and discusses homologues found in human genomic sequence databases. (PMID:12054543)
• PHF5A facilitates recognition of exons with unusual C-rich 3’ splice sites in thousands of essential genes (PMID:23651857)
• We found PHF5A, a component of the U2 snRNP mRNA splicing factor, blocks expression from recombinant Adeno-associated virus vectors (PMID:26244496)
• PHF5A-SF3B1 forms a central node for binding to splicing modulators (PMID:28541300)
• The data suggest for the first time that PHF5A is an oncoprotein that contributes to LAC progression by regulating multiple signaling pathways, and may constitute a prognostic factor and potential new therapeutic target in NSCLC. (PMID:29566713)
• Study identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in breast cancer progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones. (PMID:29700004)
• PHF5A plays an indispensable role in progressive effect of NF-kappaB pathway in HCC. (PMID:30766880)
• we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect. (PMID:30932358)
• Acetylation of PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing-mediated upregulation of KDM3A. (PMID:31054974)
• Phf5a regulates DNA repair in class switch recombination via p400 and histone H2A variant deposition. (PMID:33938017)
• PHF5A Contributes to the Maintenance of the Cancer Stem-like Phenotype in Non-Small Cell Lung Cancer by Regulating Histone Deacetylase 8. (PMID:35777798)
• Research progress and therapeutic prospect of PHF5A acting as a new target for malignant tumors. (PMID:36581580)
• [PHF5A Promotes Proliferation and Migration of Non-Small Cell Lung Cancer by Regulating of PI3K/AKT Pathway]. (PMID:36792075)
• De novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias. (PMID:37422718)
• PHF5A regulates the expression of the DOCK5 variant to promote HNSCC progression through p38 MAPK activation. (PMID:37434235)
• PHF5A is a potential diagnostic, prognostic, and immunological biomarker in pan-cancer. (PMID:37845358)
• PHF5A promotes esophageal squamous cell carcinoma progression via stabilizing VEGFA. (PMID:38429756)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	phf5a	ENSDARG00000045155
mus_musculus	Phf5a	ENSMUSG00000061360
rattus_norvegicus	Phf5a	ENSRNOG00000024170
drosophila_melanogaster	Phf5a	FBGN0031822
caenorhabditis_elegans		WBGENE00004016

Protein

Protein identifiers

PHD finger-like domain-containing protein 5A — Q7RTV0 (reviewed: Q7RTV0)

Alternative names: Splicing factor 3B-associated 14 kDa protein

All UniProt accessions (1): Q7RTV0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, PHF5A is part of the SF3B subcomplex, which is required for ‘A’ complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs. Also involved in elongation by RNA polymerase II as part of the PAF1 complex (PAF1C). PAF1C is required for maintenance of embryonic stem cell (ESC) self-renewal and cellular reprogramming of stem cells. Maintains pluripotency by recruiting and stabilizing PAF1C on pluripotency genes loci, and by regulating the expression of the pluripotency genes. Regulates the deposition of elongation-associated histone modifications, including dimethylated histone H3 ‘Lys-79’ (H3K79me2) and trimethylated histone H3 ‘Lys-36’ (H3K36me3), on PAF1C targets, self-renewal and pluripotency genes. Regulates RNA polymerase II promoter-proximal pause release of the PAF1C targets and self-renewal genes, and the levels of elongating (‘Ser-2’ phosphorylated) RNA polymerase II in their gene bodies. Regulates muscle specification in adult stem cells by stabilizing PAF1C in chromatin to promote myogenic differentiation. Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha.

Subunit / interactions. Component of the 17S U2 SnRNP complex, a ribonucleoprotein complex that contains small nuclear RNA (snRNA) U2 and a number of specific proteins. Part of the SF3B subcomplex of the 17S U2 SnRNP complex. SF3B associates with the splicing subcomplex SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP). Within the SF3B complex interacts directly with SF3B1 and SF3B3. Component of the minor spliceosome, which splices U12-type introns. Within this complex, interacts with CRIPT. Interacts (via N-terminus) with U2AF1 and SRSF5; acts to bridge the two. Interacts (via C-terminus) with EP400 and DDX1; acts to bridge the two. Interacts with the PAF1 complex (PAF1C) composed of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8. Within the PAF1C interacts directly with CDC73 and SKIC8. Interacts with RNA polymerase II.

Subcellular location. Nucleus. Nucleus speckle.

Similarity. Belongs to the PHF5 family.

RefSeq proteins (1): NP_116147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005345	PHF5	Family

Pfam: PF03660

UniProt features (37 total): binding site 12, strand 6, turn 4, helix 4, modified residue 3, site 2, region of interest 2, mutagenesis site 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

65 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5SYB	X-RAY DIFFRACTION	1.82
7Q4O	ELECTRON MICROSCOPY	2.1
7Q4P	ELECTRON MICROSCOPY	2.15
7Q3L	ELECTRON MICROSCOPY	2.21
7B9C	X-RAY DIFFRACTION	2.4
7EVO	ELECTRON MICROSCOPY	2.5
7EVN	ELECTRON MICROSCOPY	2.6
8H6L	ELECTRON MICROSCOPY	2.6
8H6K	ELECTRON MICROSCOPY	2.7
8HK1	ELECTRON MICROSCOPY	2.7
7DVQ	ELECTRON MICROSCOPY	2.89
7B0I	X-RAY DIFFRACTION	3
7B91	X-RAY DIFFRACTION	3
7B92	X-RAY DIFFRACTION	3
7OMF	X-RAY DIFFRACTION	3
7VPX	ELECTRON MICROSCOPY	3
8I0R	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
8I0V	ELECTRON MICROSCOPY	3
6EN4	X-RAY DIFFRACTION	3.08
5IFE	X-RAY DIFFRACTION	3.1
7ONB	ELECTRON MICROSCOPY	3.1
7OPI	X-RAY DIFFRACTION	3.1
7QTT	ELECTRON MICROSCOPY	3.1
9K1Y	ELECTRON MICROSCOPY	3.1
8H6E	ELECTRON MICROSCOPY	3.2
8H6J	ELECTRON MICROSCOPY	3.25
9ZE2	ELECTRON MICROSCOPY	3.26
6QX9	ELECTRON MICROSCOPY	3.28
8I0U	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7RTV0-F1	89.45	0.71

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): 17 (interaction with sf3b3); 100 (interaction with rna)

Ligand- & substrate-binding residues (12): 49; 58; 61; 72; 75; 85; 11; 23; 26; 30; 33; 46

Post-translational modifications (3): 2, 3, 94

Mutagenesis-validated functional residues (2):

Position	Phenotype
36	no apparent effect on cell growth, localization of sf3b1 protein or formation of nuclear speckles. alters the structure
36	alters the structure of the presumed branchpoint (bp) adenosine binding pocket within the splicing factor sf3b complex w

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9943411	CHD1 and CHD2 subfamily

MSigDB gene sets: 186 (showing top): E2F_Q4, E2F4DP1_01, RORA1_01, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, TGACCTY_ERR1_Q2, WEI_MYCN_TARGETS_WITH_E_BOX, NKX62_Q2, E2F1DP1_01, E2F1DP2_01, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, DODD_NASOPHARYNGEAL_CARCINOMA_UP

GO Biological Process (6): mRNA splicing, via spliceosome (GO:0000398), positive regulation of DNA-templated transcription (GO:0045893), stem cell differentiation (GO:0048863), U2-type prespliceosome assembly (GO:1903241), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (5): DNA binding (GO:0003677), RNA binding (GO:0003723), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), U2-type spliceosomal complex (GO:0005684), U2 snRNP (GO:0005686), U12-type spliceosomal complex (GO:0005689), nuclear matrix (GO:0016363), nuclear speck (GO:0016607), U2-type precatalytic spliceosome (GO:0071005), precatalytic spliceosome (GO:0071011)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
mRNA Splicing	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
CHD chromatin remodelers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
spliceosomal complex	3
RNA processing	2
nucleic acid binding	2
nuclear lumen	2
cellular anatomical structure	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cell differentiation	1
spliceosomal complex assembly	1
mRNA metabolic process	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
spliceosomal snRNP complex	1
nuclear ribonucleoprotein granule	1
U2-type spliceosomal complex	1
U1 snRNP	1
U2 snRNP	1
U4/U6 x U5 tri-snRNP complex	1
precatalytic spliceosome	1

Protein interactions and networks

STRING

2201 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHF5A	SF3B2	Q13435	996
PHF5A	SF3B3	Q15393	996
PHF5A	SF3B5	Q9BWJ5	995
PHF5A	SF3B1	O75533	994
PHF5A	SF3B4	Q15427	994
PHF5A	SF3B6	Q9Y3B4	987
PHF5A	SF3A2	Q15428	815
PHF5A	SF3A3	Q12874	785
PHF5A	SF3A1	Q15459	780
PHF5A	U2AF2	P26368	706
PHF5A	DDX46	Q7L014	667
PHF5A	PLRG1	O43660	646
PHF5A	RBM5	P52756	634
PHF5A	BUD13	Q9BRD0	628
PHF5A	RBMX2	Q9Y388	616

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
PHF5A	SF3B1	psi-mi:“MI:0914”(association)	0.730
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
SF3A2	PHF5A	psi-mi:“MI:0915”(physical association)	0.670
COMMD6	VPS26C	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
SNRPA1	U2SURP	psi-mi:“MI:0914”(association)	0.640
PPP4R2	SF3B1	psi-mi:“MI:0914”(association)	0.570
PPP4R2	SF3B1	psi-mi:“MI:2364”(proximity)	0.570
PHF5A	DMWD	psi-mi:“MI:0915”(physical association)	0.560
PHF5A	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
PHF5A	WFS1	psi-mi:“MI:0915”(physical association)	0.560
PHF5A	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
PHF5A	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
	BIN1	psi-mi:“MI:0914”(association)	0.460
Sf3a1	U2SURP	psi-mi:“MI:0915”(physical association)	0.400
CHTOP	SAP18	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (260): PHF5A (Two-hybrid), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Reconstituted Complex), PHF5A (Co-fractionation), PHF5A (Co-fractionation), SF3B4 (Co-fractionation), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS), PHF5A (Affinity Capture-MS)

ESM2 similar proteins: A0A1L1SUL6, A4QJJ7, A4QK16, A6H5F6, A6MM34, A6NH52, A6NMK7, A7M939, A8SEA1, A8W3M5, B0Z4S1, B0Z505, B0Z589, B0Z5H3, B1AR13, B1NWE8, B2LMJ1, O19048, O19137, O95639, P0C7P0, P0DI19, P46292, P60335, P83870, P83871, P98138, Q09G48, Q0G9M1, Q0WMV8, Q15365, Q1KXW1, Q332Y0, Q5E9A3, Q5FVR7, Q5R654, Q63789, Q66KE3, Q68S08, Q6DJP7

Diamond homologs: P0DI19, P83870, P83871, Q06835, Q0WMV8, Q7RTV0, Q9UTB8, Q9VMC8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PHF5A	“form complex”	SF3b	binding
PHF5A	“form complex”	“U2 snRNP complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 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
mRNA Polyadenylation	9	16.5×	4e-07
mRNA Splicing	7	16.0×	2e-05
Processing of Capped Intron-Containing Pre-mRNA	8	13.7×	1e-05
CHD1 and CHD2 subfamily	6	13.6×	3e-04
mRNA Splicing - Major Pathway	11	12.5×	2e-07
SARS-CoV-2 Infection	5	8.4×	9e-03
SARS-CoV Infections	7	8.1×	1e-03
Metabolism of RNA	9	7.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	5	48.8×	7e-06
spliceosomal complex assembly	5	47.0×	7e-06
RNA splicing	10	13.8×	1e-06
mRNA splicing, via spliceosome	9	12.9×	7e-06
mRNA processing	8	9.8×	1e-04
protein phosphorylation	7	7.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	7
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1301231	NC_000022.11:g.41468643T>C	Pathogenic
4278640	NM_032758.4(PHF5A):c.162C>A (p.Tyr54Ter)	Pathogenic
2664506	GRCh37/hg19 22q13.1-13.2(chr22:40545592-42096995)x3	Likely pathogenic

SpliceAI

534 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41460484:CTCT:C	acceptor_gain	1.0000
22:41460486:CT:C	acceptor_gain	1.0000
22:41460487:TC:T	acceptor_loss	1.0000
22:41460488:C:CC	acceptor_gain	1.0000
22:41462681:CTGA:C	donor_gain	1.0000
22:41467441:CACTT:C	donor_loss	1.0000
22:41467442:ACTTA:A	donor_loss	1.0000
22:41467443:CTTAC:C	donor_loss	1.0000
22:41467444:TTA:T	donor_loss	1.0000
22:41467445:TA:T	donor_loss	1.0000
22:41467446:A:AC	donor_gain	1.0000
22:41467446:A:AT	donor_loss	1.0000
22:41467446:ACGT:A	donor_gain	1.0000
22:41467446:ACGTC:A	donor_gain	1.0000
22:41467447:C:CC	donor_gain	1.0000
22:41467447:CGT:C	donor_gain	1.0000
22:41467447:CGTC:C	donor_gain	1.0000
22:41467447:CGTCC:C	donor_gain	1.0000
22:41467449:T:TA	donor_gain	1.0000
22:41467611:TCACC:T	acceptor_loss	1.0000
22:41467613:ACCTG:A	acceptor_loss	1.0000
22:41467614:CCTG:C	acceptor_loss	1.0000
22:41467615:C:CG	acceptor_loss	1.0000
22:41468038:AAAGC:A	donor_gain	1.0000
22:41460483:TCTCT:T	acceptor_gain	0.9900
22:41460484:CTCTC:C	acceptor_gain	0.9900
22:41460485:TCTCT:T	acceptor_gain	0.9900
22:41460496:C:CT	acceptor_gain	0.9900
22:41462680:A:AC	donor_gain	0.9900
22:41462681:C:CC	donor_gain	0.9900

AlphaMissense

720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:41460456:C:T	G92E	1.000
22:41460457:C:A	G92W	1.000
22:41460457:C:G	G92R	1.000
22:41460457:C:T	G92R	1.000
22:41460478:A:G	C85R	1.000
22:41467468:A:G	C75R	1.000
22:41467475:A:C	C72W	1.000
22:41467476:C:T	C72Y	1.000
22:41467477:A:G	C72R	1.000
22:41467517:A:C	C58W	1.000
22:41467519:A:G	C58R	1.000
22:41467536:C:T	G52E	1.000
22:41467545:C:G	C49S	1.000
22:41467546:A:G	C49R	1.000
22:41467546:A:T	C49S	1.000
22:41467554:C:T	C46Y	1.000
22:41467555:A:G	C46R	1.000
22:41467593:C:T	C33Y	1.000
22:41467594:A:G	C33R	1.000
22:41467603:A:G	C30R	1.000
22:41468141:C:T	G20E	1.000
22:41468623:A:G	C11R	1.000
22:41460434:G:C	F99L	0.999
22:41460434:G:T	F99L	0.999
22:41460436:A:G	F99L	0.999
22:41460438:A:G	L98P	0.999
22:41460442:C:G	D97H	0.999
22:41460456:C:A	G92V	0.999
22:41460459:A:G	L91P	0.999
22:41460461:A:C	N90K	0.999

dbSNP variants (sampled 300 via entrez): RS1000007362 (22:41465916 A>G), RS1000121371 (22:41459283 A>G), RS1000123302 (22:41465706 C>T), RS1000464580 (22:41459472 C>A), RS1001000809 (22:41463547 G>A), RS1001424910 (22:41470070 C>A), RS1001474426 (22:41463764 T>C), RS1001531694 (22:41464144 A>G), RS1002177191 (22:41463841 C>A), RS1002422023 (22:41463185 G>A), RS1002478488 (22:41467988 T>C), RS1002593119 (22:41467797 A>G), RS1002655680 (22:41464108 G>A,T), RS1002840216 (22:41466456 A>T), RS1003012917 (22:41461836 T>C)

Disease associations

OMIM: gene MIM:617846 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (3): syndromic craniosynostosis (MONDO:0015338), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Syndromic craniosynostosis (Orphanet:139393)

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST005232_52	Neuroticism	3.000000e-18
GCST006944_44	Experiencing mood swings	3.000000e-08
GCST006952_3	Feeling tense	2.000000e-10
GCST007576_314	Chronotype	3.000000e-12
GCST007798_114	Asthma	1.000000e-10
GCST007800_86	Asthma (childhood onset)	3.000000e-06
GCST010002_83	Refractive error	2.000000e-27
GCST010042_90	Asthma	1.000000e-12
GCST010133_13	Lamb consumption	3.000000e-08
GCST010143_2	Meat-related diet	4.000000e-08
GCST010320_52	PR interval	1.000000e-08
GCST010321_95	PR interval	6.000000e-09
GCST90000025_888	Appendicular lean mass	1.000000e-15

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0008475	mood instability measurement
EFO:0009596	feeling tense measurement
EFO:0008328	chronotype measurement
EFO:0008111	diet measurement
EFO:0004462	PR interval
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725168 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment	2
sodium arsenite	increases abundance, decreases expression	2
bisphenol S	increases expression, affects cotreatment	2
Polycyclic Aromatic Hydrocarbons	increases abundance, increases expression, affects expression, affects cotreatment	2
Valproic Acid	decreases expression	2
Asbestos, Crocidolite	increases expression, affects expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
butyraldehyde	increases expression	1
ICG 001	increases expression	1
picoxystrobin	increases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Ethanol	increases expression, affects cotreatment, increases abundance	1
Amiodarone	increases expression	1
Arsenic	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Folic Acid	increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Phenolsulfonphthalein	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	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
CHEMBL5697596	Binding	Inhibition of PHF5A (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)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice