PHC1

Summary

PHC1 (polyhomeotic homolog 1, HGNC:3182) is a protein-coding gene on chromosome 12p13.31, encoding Polyhomeotic-like protein 1 (P78364). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. It is a selective cancer dependency (DepMap: 12.0% of cell lines).

This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein.

Source: NCBI Gene 1911 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly 11, primary, autosomal recessive (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 199 total — 1 pathogenic
• Phenotypes (HPO): 18
• Cancer dependency (DepMap): dependent in 12.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004426

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3182
Approved symbol	PHC1
Name	polyhomeotic homolog 1
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	HPH1, RAE28
Ensembl gene	ENSG00000111752
Ensembl biotype	protein_coding
OMIM	602978
Entrez	1911

Gene structure

Transcript identifiers

Ensembl transcripts: 77 — 72 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000433083, ENST00000433847, ENST00000535510, ENST00000537610, ENST00000538657, ENST00000539063, ENST00000539928, ENST00000540574, ENST00000540809, ENST00000541181, ENST00000542346, ENST00000543824, ENST00000544539, ENST00000544916, ENST00000891306, ENST00000891307, ENST00000891308, ENST00000891309, ENST00000891310, ENST00000936626, ENST00000936627, ENST00000936628, ENST00000936629, ENST00000936630, ENST00000936631, ENST00000936632, ENST00000936633, ENST00000936634, ENST00000936635, ENST00000936636, ENST00000936637, ENST00000936638, ENST00000936639, ENST00000936640, ENST00000936641, ENST00000936642, ENST00000936643, ENST00000936644, ENST00000936645, ENST00000936646, ENST00000936647, ENST00000936648, ENST00000936649, ENST00000936650, ENST00000936651, ENST00000936652, ENST00000936653, ENST00000936654, ENST00000936655, ENST00000936656, ENST00000936657, ENST00000936658, ENST00000936659, ENST00000936660, ENST00000936661, ENST00000936662, ENST00000936663, ENST00000936664, ENST00000936665, ENST00000936666, ENST00000936667, ENST00000936668, ENST00000936669, ENST00000936670, ENST00000936671, ENST00000936672, ENST00000936673, ENST00000936674, ENST00000936675, ENST00000936676, ENST00000936677, ENST00000936678, ENST00000936679, ENST00000936680, ENST00000936681, ENST00000936682, ENST00000936683

RefSeq mRNA: 18 — MANE Select: NM_004426 NM_001413738, NM_001413739, NM_001413740, NM_001413741, NM_001413742, NM_001413743, NM_001413744, NM_001413745, NM_001413746, NM_001413747, NM_001413748, NM_001413749, NM_001413750, NM_001413751, NM_001413752, NM_001413753, NM_001413754, NM_004426

CCDS: CCDS8597

Canonical transcript exons

ENST00000544916 — 15 exons

Exon	Start	End
ENSE00000867847	8932563	8933350
ENSE00002215667	8914509	8914827
ENSE00002314823	8939305	8941467
ENSE00003485818	8930435	8930927
ENSE00003536004	8917630	8917791
ENSE00003541109	8936856	8936964
ENSE00003554253	8920985	8921065
ENSE00003571947	8937176	8937326
ENSE00003589850	8937829	8938060
ENSE00003591546	8934267	8934478
ENSE00003626124	8933865	8934012
ENSE00003650218	8919756	8919866
ENSE00003664889	8935124	8935238
ENSE00003677740	8922633	8922788
ENSE00003687179	8921601	8921750

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9748 / max 197.2685, expressed in 1504 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124012	2.0043	617
124013	1.6169	906
124014	1.2117	604
124009	0.7235	66
206576	0.5146	221
124017	0.2437	77
124016	0.1715	62
124015	0.1700	59
206577	0.1483	48
124018	0.0760	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.63	gold quality
adenohypophysis	UBERON:0002196	96.34	gold quality
pituitary gland	UBERON:0000007	96.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.64	gold quality
ganglionic eminence	UBERON:0004023	95.47	gold quality
cortical plate	UBERON:0005343	95.43	gold quality
ventricular zone	UBERON:0003053	95.25	gold quality
cerebellar hemisphere	UBERON:0002245	95.01	gold quality
cerebellar cortex	UBERON:0002129	94.89	gold quality
cerebellum	UBERON:0002037	94.25	gold quality
endocervix	UBERON:0000458	94.04	gold quality
body of uterus	UBERON:0009853	93.99	gold quality
left ovary	UBERON:0002119	93.68	gold quality
right lobe of thyroid gland	UBERON:0001119	93.65	gold quality
right testis	UBERON:0004534	93.54	gold quality
left lobe of thyroid gland	UBERON:0001120	93.49	gold quality
left testis	UBERON:0004533	93.43	gold quality
right ovary	UBERON:0002118	93.41	gold quality
thyroid gland	UBERON:0002046	93.17	gold quality
testis	UBERON:0000473	92.83	gold quality
ovary	UBERON:0000992	92.39	gold quality
oviduct epithelium	UBERON:0004804	91.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.40	gold quality
right coronary artery	UBERON:0001625	91.28	gold quality
right frontal lobe	UBERON:0002810	91.25	gold quality
metanephros cortex	UBERON:0010533	91.24	gold quality
tibial nerve	UBERON:0001323	91.08	gold quality
ascending aorta	UBERON:0001496	90.99	gold quality
thoracic aorta	UBERON:0001515	90.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.90	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	1179.77
E-MTAB-10018	yes	236.99
E-ANND-3	yes	4.53
E-MTAB-7008	no	297.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): POU5F1

miRNA regulators (miRDB)

100 targeting PHC1, 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-340-5P	100.00	72.50	4437
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6757-3P	99.63	66.88	1089

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• PcG complex 1, involving Rae28 and Cdt1, supports the activity of hematopoietic stem cells by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin (PMID:18650381)
• These findings reveal several cellular defects in cells carrying the PHC1 mutation and highlight the role of chromatin remodeling in the pathogenesis of PM. (PMID:23418308)
• PHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus. (PMID:33990559)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Phc1	ENSMUSG00000040669
rattus_norvegicus	Phc1	ENSRNOG00000015191
drosophila_melanogaster	l(3)mbt	FBGN0002441
drosophila_melanogaster	Sfmbt	FBGN0032475
caenorhabditis_elegans	lin-61	WBGENE00003041
caenorhabditis_elegans	mbtr-1	WBGENE00021661

Paralogs (18): SCMH1 (ENSG00000010803), MBTD1 (ENSG00000011258), SCML1 (ENSG00000047634), L3MBTL2 (ENSG00000100395), SCML2 (ENSG00000102098), THAP10 (ENSG00000129028), PHC2 (ENSG00000134686), SAMD1 (ENSG00000141858), SCML4 (ENSG00000146285), L3MBTL4 (ENSG00000154655), SFMBT1 (ENSG00000163935), PHC3 (ENSG00000173889), L3MBTL1 (ENSG00000185513), SAMD7 (ENSG00000187033), SAMD11 (ENSG00000187634), SFMBT2 (ENSG00000198879), L3MBTL3 (ENSG00000198945), SAMD13 (ENSG00000203943)

Protein

Protein identifiers

Polyhomeotic-like protein 1 — P78364 (reviewed: P78364)

Alternative names: Early development regulatory protein 1

All UniProt accessions (10): P78364, F5GZP4, F5H0T9, F5H6F5, F5H6F9, F5H6P9, H0YGK7, H0YGZ1, H0YH74, J3KQH6

UniProt curated annotations — full annotation on UniProt →

Function. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A ‘Lys-119’, rendering chromatin heritably changed in its expressibility. Required for proper control of cellular levels of GMNN expression.

Subunit / interactions. Homodimer. Component of a PRC1-like complex. Interacts with RNF2 and CBX7. Interacts with PHC2, PHC2 and BMI1.

Subcellular location. Nucleus.

Disease relevance. Microcephaly 11, primary, autosomal recessive (MCPH11) [MIM:615414] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.

RefSeq proteins (18): NP_001400667, NP_001400668, NP_001400669, NP_001400670, NP_001400671, NP_001400672, NP_001400673, NP_001400674, NP_001400675, NP_001400676, NP_001400677, NP_001400678, NP_001400679, NP_001400680, NP_001400681, NP_001400682, NP_001400683, NP_004417* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR012313	Znf_FCS	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR038603	Znf_FCS_sf	Homologous_superfamily
IPR050548	PcG_chromatin_remod_factors	Family

Pfam: PF00536, PF16616, PF21319

UniProt features (45 total): compositionally biased region 10, region of interest 7, sequence conflict 6, binding site 4, strand 4, modified residue 3, helix 3, sequence variant 2, turn 2, chain 1, domain 1, zinc finger region 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L8E	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78364-F1	51.06	0.09

Functional residue map

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

Ligand- & substrate-binding residues (4): 800; 803; 819; 823

Post-translational modifications (4): 645, 898, 922, 763

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-8953750	Transcriptional Regulation by E2F6
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 270 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, E2F_Q4, E2F4DP1_01, GCM_GSPT1, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CHESLER_BRAIN_D6MIT150_QTL_CIS, TCF4_Q5, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, MUELLER_PLURINET, E2F1DP1_01, GOBP_CELLULAR_RESPONSE_TO_RETINOIC_ACID, SOX9_B1

GO Biological Process (4): chromatin remodeling (GO:0006338), negative regulation of DNA-templated transcription (GO:0045892), cellular response to retinoic acid (GO:0071300), cellular response to leukemia inhibitory factor (GO:1990830)

GO Molecular Function (6): DNA binding (GO:0003677), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone binding (GO:0042393), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): sex chromatin (GO:0001739), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102), sperm midpiece (GO:0097225)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Cellular Senescence	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Generic Transcription Pathway	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
chromatin organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
nucleic acid binding	1
transition metal ion binding	1
protein binding	1
cation binding	1
heterochromatin	1
sex chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1
PcG protein complex	1
sperm flagellum	1

Protein interactions and networks

STRING

896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHC1	RNF2	Q99496	998
PHC1	CBX2	Q14781	997
PHC1	BMI1	P35226	997
PHC1	PCGF2	P35227	997
PHC1	R4GMX3	R4GMX3	997
PHC1	RING1	Q06587	996
PHC1	CBX4	O00257	891
PHC1	EED	O75530	891
PHC1	SUZ12	Q15022	857
PHC1	PCGF1	Q9BSM1	835
PHC1	PCGF6	Q9BYE7	826
PHC1	EZH2	Q15910	811
PHC1	CBX8	Q9HC52	797
PHC1	PHC3	Q8NDX5	788
PHC1	PHC2	Q8IXK0	787

IntAct

82 interactions, top by confidence:

A	B	Type	Score
CBX8	BMI1	psi-mi:“MI:0914”(association)	0.970
CBX7	BMI1	psi-mi:“MI:0914”(association)	0.940
PHC1	PCGF2	psi-mi:“MI:0915”(physical association)	0.920
PCGF2	PHC1	psi-mi:“MI:0915”(physical association)	0.920
BMI1	CBX4	psi-mi:“MI:0914”(association)	0.900
PHC1	BMI1	psi-mi:“MI:0915”(physical association)	0.840
PCGF2	CBX4	psi-mi:“MI:0914”(association)	0.840
CBX8	PHC1	psi-mi:“MI:0403”(colocalization)	0.830
PHC1	CBX4	psi-mi:“MI:0914”(association)	0.790
PHC1	SFMBT2	psi-mi:“MI:0915”(physical association)	0.740
RING1	CBX4	psi-mi:“MI:0914”(association)	0.730
RNF2	E2F6	psi-mi:“MI:0914”(association)	0.730
CBX8	CBX4	psi-mi:“MI:0914”(association)	0.670
RNF2	CBX4	psi-mi:“MI:0914”(association)	0.660
CBX4	YWHAB	psi-mi:“MI:0914”(association)	0.600
PHC1	SDCBP2	psi-mi:“MI:0915”(physical association)	0.560
RNF4	PHC1	psi-mi:“MI:0915”(physical association)	0.560
PHC1	FAM9A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (210): PHC1 (Two-hybrid), SIAH1 (Two-hybrid), SP100 (Two-hybrid), SUMO1 (Two-hybrid), PIAS2 (Two-hybrid), ZCCHC7 (Two-hybrid), SUMO1P1 (Two-hybrid), PHC1 (Affinity Capture-MS), SFMBT1 (Two-hybrid), UBE2I (Two-hybrid), PHC2 (Two-hybrid), PHC1 (Proximity Label-MS), PHC1 (Affinity Capture-MS), PHC1 (Affinity Capture-MS), PHC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q7JC00, A0JM64, A0JNC2, A2VE44, A4IHD9, B2C6R6, B5DE09, B8BCZ8, E7F1H9, F4JT98, O09000, O57539, P78364, Q0WVM7, Q15596, Q17BA4, Q2NLB0, Q3TCX3, Q5RDA3, Q5TP13, Q5ZL54, Q61026, Q64028, Q6GP15, Q6K271, Q6NS15, Q6PEH8, Q71SY5, Q7XYY2, Q7ZVN7, Q80TM6, Q8C7E9, Q8CHY6, Q8HXM1, Q8IZL2, Q8VCB2, Q8W234, Q90WJ3, Q924H2, Q940A7

Diamond homologs: A2A5N8, B1B1A0, D3YUG0, D3YXK1, D3ZWK4, E1C2V1, O02274, O60284, O95251, P39769, P59178, P70047, P70475, P78364, P97500, Q01538, Q05BQ5, Q1JQD9, Q1RNF8, Q29L50, Q32N90, Q3MIF2, Q4V7W5, Q5DTW2, Q5R737, Q5SVQ0, Q5VUG0, Q5VXD3, Q64028, Q6DIN3, Q6P5G3, Q6SPE9, Q6SPF0, Q7Z3H4, Q80TY4, Q810T5, Q8BLB7, Q8C8Y5, Q8CFC2, Q8CHP6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PHC1	“form complex”	“Polycomb repressive complex 1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
SUMOylation of DNA methylation proteins	9	195.0×	2e-17
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	8	77.6×	3e-12
SUMOylation of transcription cofactors	9	70.5×	4e-13
SUMOylation of RNA binding proteins	9	69.1×	4e-13
SUMOylation of DNA damage response and repair proteins	10	47.2×	4e-13
Transcriptional Regulation by E2F6	5	47.2×	2e-06
SUMOylation of chromatin organization proteins	9	46.0×	9e-12
Regulation of PTEN gene transcription	8	46.0×	2e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	143
Likely benign	17
Benign	27

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1332797	NM_004426.3(PHC1):c.100C>T (p.Arg34Ter)	Pathogenic

SpliceAI

2422 predictions. Top by Δscore:

Variant	Effect	Δscore
12:8914826:AGG:A	donor_loss	1.0000
12:8914828:GTA:G	donor_loss	1.0000
12:8917718:G:GT	donor_gain	1.0000
12:8917789:CAGG:C	donor_loss	1.0000
12:8917790:AG:A	donor_loss	1.0000
12:8917791:GGTGA:G	donor_loss	1.0000
12:8917792:G:A	donor_loss	1.0000
12:8917793:T:G	donor_loss	1.0000
12:8919752:CTA:C	acceptor_loss	1.0000
12:8919753:TA:T	acceptor_loss	1.0000
12:8919754:A:AG	acceptor_gain	1.0000
12:8919754:A:T	acceptor_loss	1.0000
12:8919754:AG:A	acceptor_gain	1.0000
12:8919755:G:A	acceptor_gain	1.0000
12:8919755:G:GT	acceptor_gain	1.0000
12:8919755:GGC:G	acceptor_gain	1.0000
12:8919755:GGCT:G	acceptor_gain	1.0000
12:8919755:GGCTC:G	acceptor_gain	1.0000
12:8919863:GCAG:G	donor_gain	1.0000
12:8919864:CAGG:C	donor_loss	1.0000
12:8919865:AG:A	donor_loss	1.0000
12:8919866:GG:G	donor_loss	1.0000
12:8919868:T:A	donor_loss	1.0000
12:8920980:A:AG	acceptor_gain	1.0000
12:8920980:AATAG:A	acceptor_gain	1.0000
12:8920981:A:G	acceptor_gain	1.0000
12:8920982:T:G	acceptor_gain	1.0000
12:8920983:A:AG	acceptor_gain	1.0000
12:8920983:A:AT	acceptor_loss	1.0000
12:8920983:AG:A	acceptor_gain	1.0000

AlphaMissense

6487 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:8917783:G:C	A36P	1.000
12:8919756:G:C	A39P	1.000
12:8919760:T:C	L40P	1.000
12:8919765:G:C	A42P	1.000
12:8919769:T:C	L43P	1.000
12:8934426:T:A	L734H	1.000
12:8934426:T:C	L734P	1.000
12:8934429:C:T	T735I	1.000
12:8934431:C:G	H736D	1.000
12:8934432:A:C	H736P	1.000
12:8934432:A:G	H736R	1.000
12:8934432:A:T	H736L	1.000
12:8934433:C:A	H736Q	1.000
12:8934433:C:G	H736Q	1.000
12:8934438:T:A	I738N	1.000
12:8934443:G:C	G740R	1.000
12:8934444:G:T	G740V	1.000
12:8934446:T:C	F741L	1.000
12:8934447:T:C	F741S	1.000
12:8934448:T:A	F741L	1.000
12:8934448:T:G	F741L	1.000
12:8934450:T:A	V742D	1.000
12:8934453:T:A	I743N	1.000
12:8934453:T:C	I743T	1.000
12:8934453:T:G	I743S	1.000
12:8934459:A:T	E745V	1.000
12:8934473:T:C	F750L	1.000
12:8934474:T:C	F750S	1.000
12:8934474:T:G	F750C	1.000
12:8934475:C:A	F750L	1.000

dbSNP variants (sampled 300 via entrez): RS1000040731 (12:8921175 GT>G), RS1000077265 (12:8930397 GTCC>G), RS1000122620 (12:8920198 C>A,G), RS1000135901 (12:8916675 T>G), RS1000145712 (12:8930680 G>A,C), RS1000227089 (12:8920774 C>T), RS1000416449 (12:8923475 C>T), RS1000423639 (12:8937510 G>C), RS1000424173 (12:8917967 G>C), RS1000981605 (12:8928572 T>G), RS1001078783 (12:8929046 A>T), RS1001110059 (12:8934624 A>G), RS1001180822 (12:8937834 A>G), RS1001248544 (12:8934871 G>A,C), RS1001257902 (12:8938159 G>C)

Disease associations

OMIM: gene MIM:602978 | disease phenotypes: MIM:615414

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly 11, primary, autosomal recessive	Moderate	Autosomal recessive
autosomal recessive primary microcephaly	Supportive	Autosomal recessive

Mondo (3): microcephaly 11, primary, autosomal recessive (MONDO:0014173), intellectual disability (MONDO:0001071), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (2): Autosomal recessive primary microcephaly (Orphanet:2512), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000582	Upslanted palpebral fissure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0003103	Abnormal cortical bone morphology
HP:0004322	Short stature
HP:0007333	Hypoplasia of the frontal lobes
HP:0010864	Severe intellectual disability

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002221_28	Cholesterol, total	2.000000e-09
GCST004235_37	Total cholesterol levels	5.000000e-11
GCST004746_37	Small cell lung carcinoma	3.000000e-06
GCST008839_289	Height	2.000000e-13
GCST009312_2	Antisaccade task score	5.000000e-08
GCST009313_7	Prepulse inhibition of the startle response	5.000000e-06
GCST012228_546	Waist-hip index	4.000000e-10
GCST012230_39	Waist-to-hip ratio adjusted for BMI	4.000000e-10
GCST90002381_487	Eosinophil count	3.000000e-12
GCST90002382_306	Eosinophil percentage of white cells	8.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0007969	cognitive inhibition measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C579935	Autosomal Recessive Primary Microcephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs187805828	PHC1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Tretinoin	decreases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1
Hydralazine	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

197 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