PHF6

Summary

PHF6 (PHD finger protein 6, HGNC:18145) is a protein-coding gene on chromosome Xq26.2, encoding PHD finger protein 6 (Q8IWS0). Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus. Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Borjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate splicing results in multiple transcript variants, encoding different isoforms.

Source: NCBI Gene 84295 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Borjeson-Forssman-Lehmann syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 354 total — 38 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001015877

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18145
Approved symbol	PHF6
Name	PHD finger protein 6
Location	Xq26.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1823, MGC14797, CENP-31
Ensembl gene	ENSG00000156531
Ensembl biotype	protein_coding
OMIM	300414
Entrez	84295

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000332070, ENST00000370799, ENST00000370800, ENST00000370803, ENST00000625464, ENST00000685047, ENST00000685553, ENST00000687496, ENST00000687834, ENST00000688598, ENST00000691812, ENST00000693759, ENST00000908869, ENST00000908870, ENST00000908871, ENST00000908872, ENST00000934663, ENST00000934664, ENST00000934665, ENST00000934666, ENST00000956398, ENST00000956399

RefSeq mRNA: 3 — MANE Select: NM_001015877 NM_001015877, NM_032335, NM_032458

CCDS: CCDS14639, CCDS14640

Canonical transcript exons

ENST00000370803 — 11 exons

Exon	Start	End
ENSE00001153856	134417169	134417302
ENSE00001153866	134415016	134415120
ENSE00001153876	134413823	134413966
ENSE00001153884	134413491	134413657
ENSE00001153891	134393909	134393952
ENSE00001153900	134393501	134393634
ENSE00001153905	134378005	134378106
ENSE00001165253	134377572	134377755
ENSE00001875599	134425661	134428790
ENSE00003822212	134425201	134425330
ENSE00003902040	134373312	134373467

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4733 / max 943.6874, expressed in 1783 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197598	20.9605	1773
197599	4.5260	1042
197600	1.3679	598
197597	0.3756	186
197601	0.2433	118

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.62	gold quality
oocyte	CL:0000023	96.64	gold quality
endothelial cell	CL:0000115	96.13	gold quality
germinal epithelium of ovary	UBERON:0001304	94.86	gold quality
secondary oocyte	CL:0000655	94.57	gold quality
ganglionic eminence	UBERON:0004023	94.50	gold quality
epithelial cell of pancreas	CL:0000083	94.33	gold quality
palpebral conjunctiva	UBERON:0001812	94.30	gold quality
epithelium of nasopharynx	UBERON:0001951	93.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.36	gold quality
caput epididymis	UBERON:0004358	93.22	gold quality
cauda epididymis	UBERON:0004360	93.01	gold quality
thymus	UBERON:0002370	92.97	gold quality
gingival epithelium	UBERON:0001949	92.91	gold quality
seminal vesicle	UBERON:0000998	92.26	gold quality
epithelium of mammary gland	UBERON:0003244	92.24	gold quality
mammary duct	UBERON:0001765	92.20	gold quality
renal medulla	UBERON:0000362	92.15	gold quality
gingiva	UBERON:0001828	92.03	gold quality
ventricular zone	UBERON:0003053	91.83	gold quality
subthalamic nucleus	UBERON:0001906	91.57	gold quality
cortical plate	UBERON:0005343	91.37	gold quality
esophagus squamous epithelium	UBERON:0006920	91.18	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.80	gold quality
pigmented layer of retina	UBERON:0001782	90.53	gold quality
skin of hip	UBERON:0001554	90.46	gold quality
parotid gland	UBERON:0001831	90.46	gold quality
middle temporal gyrus	UBERON:0002771	90.32	gold quality
inferior vagus X ganglion	UBERON:0005363	90.28	gold quality
substantia nigra pars compacta	UBERON:0001965	90.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	42.75
E-ANND-3	yes	6.66
E-MTAB-8060	no	72.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
PHF6

Upstream regulators (CollecTRI, top): PHF6

miRNA regulators (miRDB)

312 targeting PHF6, 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-4776-3P	100.00	68.73	1340
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A novel, widely expressed zinc-finger (plant homeodomain[PHD]-like finger) gene had 8 different missense and truncation mutations in 7 familial and 2 sporadic cases of BFLS (p. 661). (PMID:12415272)
• “…mutations within a novel widely expressed zinc-finger gene (PHF6) have been described in nine families with Borjesson-Forssman-Lehmann syndrome…” p. 1208 (PMID:14714741)
• “The gene, PHF6, implicated in the Borjeson-Forssman-Lehmann syndrome has recently been identified.” p. 1295 (PMID:14714754)
• A study of 9 families with PHF6 muations revealed that the phenotype is milder and more variable than previously described and evolves with age; seven missense mutations and two truncation mutations were identifed (PMID:14756673)
• By finding a PHF-6 mutation in a family with Borjeson-Forssman-Lehmann syndrome it was speculated that there is a mutational hot spot in the gene. (PMID:15241480)
• novel mutation results in exon skipping and mild Borjeson-Forssman-Lehmann syndrome (PMID:15466013)
• Success of PHF6 screening in males suspected of having Borjeson-Forssman-Lehmann syndrome is markedly increased if there is a positive family history and/or skewed X-inactivation is found in the mother. (PMID:15994862)
• we describe a novel mutation that changes a residue within the first plant homeodomain zinc finger motif of PHF6 in a family with classical features of Borjeson-Forssman-Lehmann syndrome (PMID:19264739)
• these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease. (PMID:20228800)
• Borjeson-Forssman-Lehmann syndrome (BFLS) may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-cell acute lymphoblastic leukemia. (PMID:20806366)
• PHF6 as a tumor suppressor gene mutated in acute myeloid leukemias (AML) and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors. (PMID:21030981)
• Our data suggest that PHF6 mutation might play a role in tumorigenesis not only of T-cell acute lymphoblatic leukemia, but also acute myelogenous leukemia and hepatocellular carcinoma. (PMID:21736506)
• in T-cell acute lymphoblastic leukemia, PHF6 mutations are a recurrent genetic abnormality associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214. (PMID:21880637)
• PHF6 interacts with the nucleosome remodeling and deacetylation complex and is localized primarily in the nucleoplasm and nucleolus. (PMID:22720776)
• Data suggest that mutations of PHF6 are associated with chronic myeloid leukemia (CML) progression. (PMID:22928734)
• These results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression. (PMID:23229552)
• The findings show that de novo mutations in PHF6 in females result in a recognisable phenotype which overlap with Borjeson-Forssman-Lehmann syndrome but also has additional distinct features, thus adding a new facet to this disorder. (PMID:24092917)
• Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. (PMID:24380767)
• these data support the hypothesis that PHF6 may function as a transcriptional repressor using its ePHD domains binding to the promoter region of its repressed gene (PMID:24554700)
• Recurrent microdeletion was detected in Xq26.3, causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. (PMID:24674452)
• The PHF6 tumor suppressor gene was targeted in acute lymphoblastic leukemia by microRNA-128-3p. (PMID:24895337)
• Female phenotypes of Borjeson-Forssman-Lehmann syndrome patients with PHF6 mutations (PMID:25099957)
• Our RBBP4-PHF6 complex structure provides insights into the molecular basis of PHF6-NuRD complex interaction and implicates a role for PHF6 in chromatin structure modulation and gene regulation. (PMID:25601084)
• Phf6 is a “lineage-specific” cancer gene that plays opposing roles in developmentally distinct hematopoietic malignancies. (PMID:25737277)
• Our results suggest that PHF6 may function as an oncogenic factor in several types of cancer. We also hypothesize that PHF6 may also play its role in a tissue-specific manner. Our findings suggest further investigations regarding the exact role of PHF6 in tumor types. (PMID:26561469)
• PHF6 localizes to the sub-nucleolar fibrillar center where it binds to rDNA-coding sequences. PHF6 mediates the overall levels of ribosome biogenesis within a cell. (PMID:27165002)
• PHF6 defects most likely result in their loss of function and have a substantial effect on the evolution into the aggressive types of myeloid neoplasms, associated with other concomitant genetic defects including RUNX1 mutations (PMID:27479181)
• The mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Borjeson-Forssman-Lehmann syndrome. (PMID:27633282)
• PHF6 mutations occur at a low frequency in pediatric acute myeloid leukemia in both female and male patients (PMID:27885656)
• EZH2 mutations coexisted with mutations of NOTCH1, IL7R, and PHF6 in the two Adult T-cell Acute Lymphoblastic Leukemia patients, and they responded poorly to chemotherapy and experienced difficult clinical histories and inferior outcomes (PMID:28747286)
• PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases. All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6 mutations. (PMID:30530780)
• PHF6 mutations are early events and drivers of leukemia stem cell activity in the pathogenesis of T-cell acute lymphoblastic leukemia. (PMID:30567843)
• PHF6 was significantly elevated in hepatocellular carcinoma (HCC) tissues and positively correlated with TNM stage, differentiation, and lymph node metastasis. Silencing PHF6 significantly inhibited cell proliferation, colony formation, and migration in HCC cells. Furthermore, silencing PHF6 obviously increased E-cadherin and decreased Vimentin expression. (PMID:30888215)
• Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau (PMID:31562564)
• PHF6 promotes non-homologous end joining and G2 checkpoint recovery. (PMID:31782600)
• Grandparental genotyping enhances exome variant interpretation. (PMID:32027463)
• Plant homeodomain finger protein 6 in the regulation of normal and malignant hematopoiesis. (PMID:32398456)
• A Novel Missense Variant in PHF6 Gene Causing Borjeson-Forssman-Lehman Syndrome. (PMID:32399860)
• Upregulated Plant Homeodomain Finger Protein 6 Promotes Extracellular Matrix Degradation in Intervertebral Disc Degeneration Based on Microarray Analysis. (PMID:32453232)
• The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes. (PMID:32735658)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	phf6	ENSDARG00000004046
mus_musculus	Phf6	ENSMUSG00000025626
rattus_norvegicus	Phf6	ENSRNOG00000002276
drosophila_melanogaster	pie	FBGN0005683
drosophila_melanogaster	Phf7	FBGN0031091

Paralogs (3): PHF7 (ENSG00000010318), G2E3 (ENSG00000092140), PHF11 (ENSG00000136147)

Protein

Protein identifiers

PHD finger protein 6 — Q8IWS0 (reviewed: Q8IWS0)

Alternative names: PHD-like zinc finger protein

All UniProt accessions (6): Q8IWS0, A0A0D9SGE8, A0A8I5KVG8, A0A8I5KWC2, A0A8I5QJH7, Q5JRC6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription.

Subunit / interactions. Interacts with UBTF. Interacts with the NuRD complex component RBBP4 (via the nucleolar localization motif), the interaction mediates transcriptional repression activity.

Subcellular location. Nucleus. Nucleolus. Chromosome. Centromere. Kinetochore.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Boerjeson-Forssman-Lehmann syndrome (BFLS) [MIM:301900] An X-linked recessive disorder characterized by moderate to severe intellectual disability, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PHD-type zinc finger 1 mediates both nucleolar localization and interaction with UBTF. The ePHD2 domain folds as an integrated structural module comprizing the C2HC pre-PHD-type 2 zinc finger and the PHD-type 2 zinc finger. It mediates non-specific binding to dsDNA, but doesn’t bind histones in contrast to many PHD-type zinc fingers.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8IWS0-1	1, PHF6a, PHF6b	yes
Q8IWS0-2	2
Q8IWS0-3	3
Q8IWS0-4	4
Q8IWS0-5	5

RefSeq proteins (3): NP_001015877, NP_115711, NP_115834 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001965	Znf_PHD	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR034732	EPHD	Domain
IPR051188	PHD-type_Zinc_Finger	Family

Pfam: PF13771

UniProt features (53 total): modified residue 8, sequence variant 6, helix 6, strand 6, splice variant 5, zinc finger region 4, region of interest 4, short sequence motif 3, compositionally biased region 3, turn 3, cross-link 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4NN2	X-RAY DIFFRACTION	1.47
4R7A	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWS0-F1	73.45	0.33

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 (10): 2, 138, 145, 155, 183, 199, 358, 173, 227, 146

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9940951	Interaction of NuRD complexes with transcription factors

MSigDB gene sets: 385 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, TTTGTAG_MIR520D, SP3_Q3, AACYNNNNTTCCS_UNKNOWN, RACCACAR_AML_Q6, AAAYRNCTG_UNKNOWN, GTGCCTT_MIR506, NFKB_C, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, WANG_LMO4_TARGETS_DN, AML_Q6, GGARNTKYCCA_UNKNOWN, TGTGTGA_MIR377, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_BLASTOCYST_DEVELOPMENT

GO Biological Process (2): negative regulation of transcription by RNA polymerase II (GO:0000122), blastocyst hatching (GO:0001835)

GO Molecular Function (12): DNA binding (GO:0003677), RNA binding (GO:0003723), zinc ion binding (GO:0008270), tubulin binding (GO:0015631), enzyme binding (GO:0019899), histone binding (GO:0042393), histone deacetylase binding (GO:0042826), ribonucleoprotein complex binding (GO:0043021), phosphoprotein binding (GO:0051219), scaffold protein binding (GO:0097110), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): kinetochore (GO:0000776), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
NuRD complex assembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
intracellular membraneless organelle	3
nucleic acid binding	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blastocyst development	1
hatching	1
transition metal ion binding	1
cytoskeletal protein binding	1
enzyme binding	1
protein-containing complex binding	1
binding	1
cation binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
chromosomal region	1

Protein interactions and networks

STRING

2724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHF6	TLX3	O43711	896
PHF6	TLX1	P31314	841
PHF6	PHF8	Q9UPP1	839
PHF6	KMT2A	Q03164	838
PHF6	HCFC1	P51610	820
PHF6	RUNX1	Q01196	799
PHF6	FLT3	P36888	772
PHF6	ZRSR2	Q15696	768
PHF6	ASXL1	Q8IXJ9	745
PHF6	IKZF1	Q13422	743
PHF6	LEO1	Q8WVC0	731
PHF6	CTR9	Q6PD62	731
PHF6	U2AF1	Q01081	727
PHF6	CDC73	Q6P1J9	723
PHF6	SETBP1	Q9Y6X0	718

IntAct

74 interactions, top by confidence:

A	B	Type	Score
AXIN1	APC	psi-mi:“MI:0914”(association)	0.850
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
AP3M1	AP3B1	psi-mi:“MI:0914”(association)	0.640
CPLX2	CPLX1	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
LTK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
EDEM1	P4HB	psi-mi:“MI:0914”(association)	0.350
Prpf3	PRPF4	psi-mi:“MI:0914”(association)	0.350
ORC1	ZNF768	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
Arhgap1	ZNF207	psi-mi:“MI:0914”(association)	0.350
SYDE1	APBB1	psi-mi:“MI:0914”(association)	0.350
TP53BP1	BCKDK	psi-mi:“MI:0914”(association)	0.350
N	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
SRPK2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
KLF16		psi-mi:“MI:0914”(association)	0.350
TEK	KIF2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (201): RBBP4 (Affinity Capture-Western), HDAC1 (Affinity Capture-Western), CHD4 (Affinity Capture-Western), PHF6 (Affinity Capture-Western), PHF6 (Affinity Capture-Western), CHD4 (Affinity Capture-MS), CHD3 (Affinity Capture-MS), RBBP4 (Affinity Capture-MS), RBBP7 (Affinity Capture-MS), HIST1H1C (Affinity Capture-MS), HIST1H2BB (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), SNRNP200 (Affinity Capture-MS), PRPF8 (Affinity Capture-MS), HNRNPA2B1 (Affinity Capture-MS)

ESM2 similar proteins: A0A286Y9D1, B2RRD7, C0SUU8, E1C2V1, G5E8P1, O75164, O94880, O95696, P0CB22, P55201, Q08DR0, Q13415, Q15910, Q28D84, Q4R381, Q4V863, Q58DC8, Q5R5Z2, Q5RBG4, Q5RD88, Q5TKR9, Q5XI06, Q61188, Q63ZP1, Q6AXW4, Q6GQJ2, Q6IE82, Q803A0, Q8BLB7, Q8BRB7, Q8BW72, Q8BZ21, Q8CHK4, Q8IWS0, Q8VCD7, Q8WML3, Q8WYB5, Q92613, Q92794, Q92993

Diamond homologs: A6H5X4, F4I443, O08550, O14686, P55200, Q03164, Q08DR0, Q2HJ93, Q4R9C4, Q5F4A1, Q5I0E2, Q5I0J8, Q5R5Z2, Q5RJY2, Q6PDK2, Q7L622, Q8BRH4, Q8BVM9, Q8IWS0, Q8NEZ4, Q9D4J7, Q9UIL8, Q9UMN6, A0A0R4I9Y1, B6VQ60, O15344, P10862, P15533, P20659, P82457, Q0PF16, Q1ACD5, Q1ACD6, Q1ACD7, Q24742, Q2YEM8, Q2YEM9, Q2YEN0, Q2YEN2, Q3UWZ0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PHF6	down-regulates	UBTF	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
Signaling by ALK fusions and activated point mutants	7	14.4×	4e-04
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	6	12.0×	3e-03
Estrogen-dependent gene expression	7	7.2×	8e-03
Ub-specific processing proteases	9	6.5×	3e-03
Diseases of signal transduction by growth factor receptors and second messengers	8	6.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	19.2×	5e-04
positive regulation of fibroblast proliferation	5	16.2×	3e-03
cell surface receptor protein tyrosine kinase signaling pathway	7	13.4×	5e-04
ribosomal small subunit biogenesis	5	12.5×	8e-03
positive regulation of protein ubiquitination	5	11.7×	8e-03
negative regulation of translation	5	10.8×	8e-03
cytoplasmic translation	5	10.2×	1e-02
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	9	7.8×	8e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — ALL, AML, BL, LUAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	19
Uncertain significance	101
Likely benign	74
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11063	NM_001015877.2(PHF6):c.1024C>T (p.Arg342Ter)	Pathogenic
11064	NM_001015877.2(PHF6):c.296G>T (p.Cys99Phe)	Pathogenic
11065	NM_001015877.2(PHF6):c.700A>G (p.Lys234Glu)	Pathogenic
11066	NM_001015877.2(PHF6):c.134G>A (p.Cys45Tyr)	Pathogenic
11067	NM_001015877.2(PHF6):c.686A>G (p.His229Arg)	Pathogenic
11068	NM_001015877.2(PHF6):c.2T>C (p.Met1Thr)	Pathogenic
11069	NM_001015877.2(PHF6):c.769A>G (p.Arg257Gly)	Pathogenic
11070	NM_001015877.2(PHF6):c.22A>T (p.Lys8Ter)	Pathogenic
11071	NM_001015877.2(PHF6):c.139-8A>G	Pathogenic
11072	NM_001015877.2(PHF6):c.27dup (p.Gly10fs)	Pathogenic
1319370	NM_001015877.2(PHF6):c.85G>T (p.Gly29Ter)	Pathogenic
1320220	NM_001015877.2(PHF6):c.415G>T (p.Glu139Ter)	Pathogenic
139557	NM_001015877.2(PHF6):c.914G>T (p.Cys305Phe)	Pathogenic
1710152	NM_001015877.2(PHF6):c.890G>T (p.Cys297Phe)	Pathogenic
208718	NM_001015877.2(PHF6):c.915_916delinsAA (p.Cys305_Gly306delinsTer)	Pathogenic
218375	NM_001015877.2(PHF6):c.418G>A (p.Ala140Thr)	Pathogenic
2427038	NC_000023.10:g.(?133511648)(133559360_?)del	Pathogenic
242879	NM_001015877.2(PHF6):c.255C>A (p.Cys85Ter)	Pathogenic
2474433	NM_001015877.2(PHF6):c.241-5_255del	Pathogenic
2502441	NM_001015877.2(PHF6):c.743G>T (p.Gly248Val)	Pathogenic
2769148	NM_001015877.2(PHF6):c.346C>T (p.Arg116Ter)	Pathogenic
2902140	NM_001015877.2(PHF6):c.385C>T (p.Arg129Ter)	Pathogenic
3242558	NM_001015877.2(PHF6):c.417A>T (p.Glu139Asp)	Pathogenic
3337450	NM_001015877.2(PHF6):c.464C>G (p.Ser155Ter)	Pathogenic
3342748	NM_001015877.2(PHF6):c.88C>T (p.Gln30Ter)	Pathogenic
3371391	NM_001015877.2(PHF6):c.375-1G>A	Pathogenic
4795937	NM_001015877.2(PHF6):c.181dup (p.Ser61fs)	Pathogenic
4812866	NM_001015877.2(PHF6):c.-46-2A>G	Pathogenic
4838626	NM_001015877.2(PHF6):c.667G>T (p.Glu223Ter)	Pathogenic
488410	NM_001015877.2(PHF6):c.673C>T (p.Arg225Ter)	Pathogenic

SpliceAI

1554 predictions. Top by Δscore:

Variant	Effect	Δscore
X:134378003:A:AG	acceptor_gain	1.0000
X:134378004:G:GG	acceptor_gain	1.0000
X:134378021:T:TA	acceptor_gain	1.0000
X:134378103:GCTG:G	donor_gain	1.0000
X:134393495:CTGTA:C	acceptor_loss	1.0000
X:134393496:TGTA:T	acceptor_loss	1.0000
X:134393497:GTAG:G	acceptor_loss	1.0000
X:134393498:TAGAT:T	acceptor_loss	1.0000
X:134393499:A:AG	acceptor_gain	1.0000
X:134393499:A:G	acceptor_loss	1.0000
X:134393500:G:GG	acceptor_gain	1.0000
X:134393500:GAT:G	acceptor_gain	1.0000
X:134393500:GATGT:G	acceptor_gain	1.0000
X:134393625:G:GT	donor_gain	1.0000
X:134393626:A:T	donor_gain	1.0000
X:134393635:G:GG	donor_gain	1.0000
X:134393905:ATAG:A	acceptor_gain	1.0000
X:134394002:T:G	donor_gain	1.0000
X:134394002:T:TG	donor_gain	1.0000
X:134394006:G:GG	donor_gain	1.0000
X:134394012:A:G	donor_gain	1.0000
X:134413486:A:G	acceptor_gain	1.0000
X:134413487:GCA:G	acceptor_gain	1.0000
X:134413644:A:T	donor_gain	1.0000
X:134413654:CTAT:C	donor_gain	1.0000
X:134413654:CTATG:C	donor_loss	1.0000
X:134413655:TAT:T	donor_gain	1.0000
X:134413656:ATGT:A	donor_loss	1.0000
X:134413657:TGTA:T	donor_loss	1.0000
X:134413658:G:GG	donor_gain	1.0000

AlphaMissense

2415 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:134377666:T:C	C17R	1.000
X:134377673:T:C	F19S	1.000
X:134377675:T:C	C20R	1.000
X:134377750:T:A	C45S	1.000
X:134377750:T:C	C45R	1.000
X:134377751:G:C	C45S	1.000
X:134377752:C:G	C45W	1.000
X:134378059:T:C	F65L	1.000
X:134378060:T:C	F65S	1.000
X:134378061:T:A	F65L	1.000
X:134378061:T:G	F65L	1.000
X:134378075:T:A	V70D	1.000
X:134378083:G:A	E73K	1.000
X:134378093:G:C	R76T	1.000
X:134378094:A:C	R76S	1.000
X:134378094:A:T	R76S	1.000
X:134378095:G:C	G77R	1.000
X:134378096:G:A	G77D	1.000
X:134378096:G:T	G77V	1.000
X:134378105:T:C	L80P	1.000
X:134393504:T:A	C82S	1.000
X:134393504:T:C	C82R	1.000
X:134393505:G:C	C82S	1.000
X:134393506:T:G	C82W	1.000
X:134393538:G:A	G93D	1.000
X:134393540:T:A	C94S	1.000
X:134393540:T:C	C94R	1.000
X:134393541:G:A	C94Y	1.000
X:134393541:G:C	C94S	1.000
X:134393541:G:T	C94F	1.000

dbSNP variants (sampled 300 via entrez): RS1000047902 (X:134412807 T>C), RS1000049531 (X:134409914 G>T), RS1000075359 (X:134410038 C>T), RS1000219320 (X:134388548 T>C), RS1000223727 (X:134377816 G>C), RS1000246338 (X:134401389 T>C), RS1000320755 (X:134391232 C>G), RS1000337999 (X:134390648 A>G), RS1000342719 (X:134374500 G>A), RS1000439077 (X:134389178 A>G), RS1000582556 (X:134372503 G>C), RS1000636369 (X:134404645 CAAAA>C), RS1000637735 (X:134401165 A>G), RS1000651489 (X:134373058 T>C), RS1000753456 (X:134427733 A>G)

Disease associations

OMIM: gene MIM:300414 | disease phenotypes: MIM:301900, MIM:182601

GenCC curated gene-disease

Disease	Classification	Inheritance
Borjeson-Forssman-Lehmann syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Borjeson-Forssman-Lehmann syndrome	Definitive	XL

Mondo (7): Borjeson-Forssman-Lehmann syndrome (MONDO:0010537), intellectual disability (MONDO:0001071), hereditary spastic paraplegia 4 (MONDO:0008438), obesity disorder (MONDO:0011122), neuroblastoma (MONDO:0005072), pulmonary arterial hypertension (MONDO:0015924), mega-cisterna magna (MONDO:0019953)

Orphanet (9): Borjeson-Forssman-Lehmann syndrome (Orphanet:127), Autosomal dominant spastic paraplegia type 4 (Orphanet:100985), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Neuroblastoma (Orphanet:635), Pulmonary arterial hypertension (Orphanet:182090), Mega-cisterna magna (Orphanet:97252), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000135	Hypogonadism
HP:0000202	Orofacial cleft
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000336	Prominent supraorbital ridges
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000574	Thick eyebrow
HP:0000581	Blepharophimosis
HP:0000639	Nystagmus
HP:0000771	Gynecomastia
HP:0000823	Delayed puberty
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001382	Joint hypermobility
HP:0001419	X-linked recessive inheritance
HP:0001513	Obesity
HP:0001769	Broad foot
HP:0001831	Short toe

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
C536575	Borjeson-Forssman-Lehmann syndrome (supp.)
C536865	Spastic paraplegia 4, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465329 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	Kd	2014	nM	CHEMBL3752910
5.70	ED50	2014	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 23 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149909: Binding affinity to human PHF6 incubated for 45 mins by Kinobead based pull down assay	kd	2.0143	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Coal	decreases expression, increases abundance	1
Demecolcine	decreases expression	1
Diethylstilbestrol	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Endosulfan	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	increases expression	1
Ivermectin	decreases expression	1
Ketoconazole	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5336063	Binding	Inhibition of PHF6 peptide (unknown origin) aggregation at 10 uM measured after 3 hrs by thioflavin T fluorescence based fluorimetric analysis relative to control	Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer’s disease. — Eur J Med Chem

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 2 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1BC	Abcam HEK293 PHF6 KO	Transformed cell line	Female
CVCL_B2AK	Abcam HeLa PHF6 KO	Cancer cell line	Female
CVCL_TD17	HAP1 PHF6 (-) 1	Cancer cell line	Male
CVCL_TD18	HAP1 PHF6 (-) 2	Cancer cell line	Male
CVCL_TD19	HAP1 PHF6 (-) 3	Cancer cell line	Male
CVCL_TD20	HAP1 PHF6 (-) 4	Cancer cell line	Male
CVCL_UL41	USCi003-A	Induced pluripotent stem cell
CVCL_UL42	USCi004-A	Induced pluripotent stem cell
CVCL_XR57	HAP1 PHF6 (-) 5	Cancer cell line	Male
CVCL_XR58	HAP1 PHF6 (-) 6	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders