RNF14

Summary

RNF14 (ring finger protein 14, HGNC:10058) is a protein-coding gene on chromosome 5q31.3, encoding E3 ubiquitin-protein ligase RNF14 (Q9UBS8). E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes.

The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This protein interacts with androgen receptor (AR) and may function as a coactivator that induces AR target gene expression in prostate. A dominant negative mutant of this gene has been demonstrated to inhibit the AR-mediated growth of prostate cancer. This protein also interacts with class III ubiquitin-conjugating enzymes (E2s) and may act as a ubiquitin-ligase (E3) in the ubiquitination of certain nuclear proteins. Six alternatively spliced transcript variants encoding two distinct isoforms have been reported.

Source: NCBI Gene 9604 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 72 total — 1 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_004290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10058
Approved symbol	RNF14
Name	ring finger protein 14
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	ARA54, HFB30, TRIAD2
Ensembl gene	ENSG00000013561
Ensembl biotype	protein_coding
OMIM	605675
Entrez	9604

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 50 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000347642, ENST00000356143, ENST00000394514, ENST00000394519, ENST00000394520, ENST00000502341, ENST00000506004, ENST00000506822, ENST00000506938, ENST00000507163, ENST00000507291, ENST00000511961, ENST00000512565, ENST00000513019, ENST00000514620, ENST00000515613, ENST00000905396, ENST00000905397, ENST00000905398, ENST00000905399, ENST00000905400, ENST00000905401, ENST00000905402, ENST00000905403, ENST00000905404, ENST00000905405, ENST00000905406, ENST00000905407, ENST00000905408, ENST00000905409, ENST00000905410, ENST00000905411, ENST00000905412, ENST00000905413, ENST00000905414, ENST00000905415, ENST00000939446, ENST00000939447, ENST00000939448, ENST00000939449, ENST00000963023, ENST00000963024, ENST00000963025, ENST00000963026, ENST00000963027, ENST00000963028, ENST00000963029, ENST00000963030, ENST00000963031, ENST00000963032, ENST00000963033, ENST00000963034, ENST00000963035

RefSeq mRNA: 6 — MANE Select: NM_004290 NM_001201365, NM_004290, NM_183398, NM_183399, NM_183400, NM_183401

CCDS: CCDS4270, CCDS4271

Canonical transcript exons

ENST00000394520 — 9 exons

Exon	Start	End
ENSE00001518701	141970704	141970877
ENSE00001813515	141987733	141990292
ENSE00002084844	141969105	141969167
ENSE00002279747	141974804	141974955
ENSE00003467557	141973583	141973742
ENSE00003566362	141980123	141980351
ENSE00003681329	141983380	141983552
ENSE00003785210	141978303	141978830
ENSE00003789835	141984803	141984933

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 96.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5931 / max 333.0994, expressed in 1795 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59061	13.3664	1772
59060	1.8878	1079
59063	1.4619	937
59062	0.8686	603
59059	0.0085	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	96.86	gold quality
endothelial cell	CL:0000115	96.58	gold quality
oocyte	CL:0000023	96.03	gold quality
secondary oocyte	CL:0000655	95.95	gold quality
right testis	UBERON:0004534	95.20	gold quality
right adrenal gland cortex	UBERON:0035827	95.06	gold quality
left testis	UBERON:0004533	94.90	gold quality
calcaneal tendon	UBERON:0003701	94.85	gold quality
right adrenal gland	UBERON:0001233	94.80	gold quality
islet of Langerhans	UBERON:0000006	94.71	gold quality
rectum	UBERON:0001052	94.45	gold quality
left adrenal gland	UBERON:0001234	94.39	gold quality
adrenal gland	UBERON:0002369	94.04	gold quality
left adrenal gland cortex	UBERON:0035825	93.91	gold quality
popliteal artery	UBERON:0002250	93.85	gold quality
tibial artery	UBERON:0007610	93.85	gold quality
prefrontal cortex	UBERON:0000451	93.75	gold quality
right coronary artery	UBERON:0001625	93.72	gold quality
descending thoracic aorta	UBERON:0002345	93.72	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.58	gold quality
stromal cell of endometrium	CL:0002255	93.44	gold quality
right atrium auricular region	UBERON:0006631	93.44	gold quality
testis	UBERON:0000473	93.41	gold quality
heart left ventricle	UBERON:0002084	93.39	gold quality
aorta	UBERON:0000947	93.38	gold quality
adrenal cortex	UBERON:0001235	93.28	gold quality
cardiac ventricle	UBERON:0002082	93.15	gold quality
gastrocnemius	UBERON:0001388	93.04	gold quality
left coronary artery	UBERON:0001626	93.03	gold quality
mucosa of stomach	UBERON:0001199	92.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.49

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CCND1	Activation

miRNA regulators (miRDB)

105 targeting RNF14, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540

Literature-anchored findings (GeneRIF, showing 8)

• dominant-negative AR coregulator can suppress AR transactivation and cell proliferation in prostate cancer cells (PMID:11673464)
• ARA54 role in prostate carcinoma progression may in may involve function as androgen receptor coactivator and focal adhesion protein (PMID:12772188)
• ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. (PMID:17082327)
• Dual functional roles for ARA54 as an AR coregulator directly and as a mediator for the suppressive effect of hnRNP A1 indirectly. (PMID:17110431)
• mRNA expression of ARA54 correlates with that of cyclin D1 in human colon carcinoma cells, indicating that ARA54 is not only involved in the regulation of cyclin D1 expression in cultured cell lines but also in clinical cancer specimens. (PMID:17510080)
• Differential localization of ARA54 may play an important role in testicular development and spermatogenesis in humans. (PMID:17919607)
• Ring Finger Protein 14 (RNF14) is a binding partner for all TCF/LEF transcription factors. (PMID:23449499)
• RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks. (PMID:37951216)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf14	ENSDARG00000043905
danio_rerio	RNF14	ENSDARG00000078683
danio_rerio		ENSDARG00000091727
danio_rerio	RNF14	ENSDARG00000104631
mus_musculus	Rnf14	ENSMUSG00000060450
rattus_norvegicus	Rnf14	ENSRNOG00000045637
caenorhabditis_elegans		WBGENE00018964
caenorhabditis_elegans		WBGENE00018966

Paralogs (9): ANKIB1 (ENSG00000001629), RNF19A (ENSG00000034677), RNF19B (ENSG00000116514), RNF144B (ENSG00000137393), RNF217 (ENSG00000146373), RNF144A (ENSG00000151692), ARIH1 (ENSG00000166233), ARIH2 (ENSG00000177479), PRKN (ENSG00000185345)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF14 — Q9UBS8 (reviewed: Q9UBS8)

Alternative names: Androgen receptor-associated protein 54, HFB30, RING finger protein 14

All UniProt accessions (12): Q9UBS8, B7Z229, B7Z3J5, D6R988, D6R996, D6RA38, D6RAS4, D6RBK4, D6RBU3, D6RDK2, D6RDU6, E7EP22

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes. Recruited to stalled ribosomes by the ribosome collision sensor GCN1 and mediates ‘Lys-6’-linked ubiquitination of target proteins, leading to their degradation. Mediates ubiquitination of EEF1A1/eEF1A and ETF1/eRF1 translation factors on stalled ribosomes, leading to their degradation. Also catalyzes ubiquitination of ribosomal proteins RPL0, RPL1, RPL12, RPS13 and RPS17. Specifically required to resolve RNA-protein cross-links caused by reactive aldehydes, which trigger translation stress by stalling ribosomes: acts by catalying ‘Lys-6’-linked ubiquitination of RNA-protein cross-links, leading to their removal by the ATP-dependent unfoldase VCP and subsequent degradation by the proteasome. Independently of its function in the response to stalled ribosomes, acts as a regulator of transcription in Wnt signaling via its interaction with TCF transcription factors (TCF7/TCF1, TCF7L1/TCF3 and TCF7L2/TCF4). May also play a role as a coactivator for androgen- and, to a lesser extent, progesterone-dependent transcription.

Subunit / interactions. Interacts with GCN1; interaction takes place in response to ribosome collisions and is required for ubiquitination of EEF1A1/eEF1A. Interacts with the ubiquitin-conjugating enzymes UBE2E1 and UBE2E2. Interacts with AR/androgen receptor. Interacts with TCF7/TCF1, TCF7L1/TCF3 and TCF7L2/TCF4; promoting Wnt signaling.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed.

Post-translational modifications. RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination.

Domain organisation. The N-terminal destruction box (D-box) acts as a recognition signal for degradation via the ubiquitin-proteasome pathway. Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RBR family. RNF14 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBS8-1	1	yes
Q9UBS8-2	2

RefSeq proteins (6): NP_001188294, NP_004281, NP_899645, NP_899646, NP_899647, NP_899648 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR002867	IBR_dom	Domain
IPR006575	RWD_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR031127	E3_UB_ligase_RBR	Family
IPR031128	RNF14_RING-HC_Zfn	Domain
IPR044066	TRIAD_supradom	Domain
IPR047548	Rcat_RBR_RNF14	Domain

Pfam: PF01485, PF05773, PF22191

UniProt features (39 total): binding site 24, zinc finger region 3, mutagenesis site 2, region of interest 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence conflict 1, coiled-coil region 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBS8-F1	83.00	0.45

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 (1): 417

Ligand- & substrate-binding residues (24): 220; 223; 238; 240; 243; 246; 265; 270; 309; 314; 329; 332 …

Post-translational modifications (1): 348

Mutagenesis-validated functional residues (2):

Position	Phenotype
220	abolished e3 ubiquitin-protein ligase activity. loss of interaction with ube2e2 and of autoubiquitination.
417	abolished e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 240 (showing top): FXR_IR1_Q6, ELVIDGE_HYPOXIA_DN, MORF_MSH3, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, CGGAARNGGCNG_UNKNOWN, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CAGCTG_AP4_Q5

GO Biological Process (14): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), protein ubiquitination (GO:0016567), androgen receptor signaling pathway (GO:0030521), positive regulation of DNA-templated transcription (GO:0045893), regulation of androgen receptor signaling pathway (GO:0060765), regulation of canonical Wnt signaling pathway (GO:0060828), rescue of stalled cytosolic ribosome (GO:0072344), protein K6-linked ubiquitination (GO:0085020), protein-RNA covalent cross-linking repair (GO:0160127), translational elongation (GO:0006414), translational termination (GO:0006415)

GO Molecular Function (10): transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), ubiquitin-like protein transferase activity (GO:0019787), ubiquitin conjugating enzyme binding (GO:0031624), nuclear androgen receptor binding (GO:0050681), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytosolic ribosome (GO:0022626)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	2
regulation of DNA-templated transcription	2
translation	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein modification by small protein conjugation	1
nuclear receptor-mediated steroid hormone signaling pathway	1
positive regulation of RNA biosynthetic process	1
androgen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
cytoplasmic translational elongation	1
ribosome disassembly	1
protein polyubiquitination	1
rescue of stalled cytosolic ribosome	1
macromolecule biosynthetic process	1
protein-containing complex disassembly	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
transition metal ion binding	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
ubiquitin-like protein conjugating enzyme binding	1
nuclear receptor binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF14	NCOA4	Q13772	860
RNF14	A0A2R8Y4M4	A0A2R8Y4M4	815
RNF14	AR	P10275	810
RNF14	TGFB1I1	O43294	747
RNF14	RNF216	Q9NWF9	603
RNF14	NCOA2	Q15596	597
RNF14	RNF6	Q9Y252	517
RNF14	A0A0A6YYI9	A0A0A6YYI9	512
RNF14	TMF1	P82094	506
RNF14	GTF2H2	Q13888	495
RNF14	CCNT2	O60583	492
RNF14	NCOA1	Q15788	492
RNF14	MN1	Q10571	491
RNF14	RBM14	Q96PK6	491
RNF14	POLR2B	P30876	491

IntAct

48 interactions, top by confidence:

A	B	Type	Score
RNF14	UBE2D4	psi-mi:“MI:0915”(physical association)	0.740
UBE2D4	RNF14	psi-mi:“MI:0915”(physical association)	0.740
DACH1	RNF14	psi-mi:“MI:0915”(physical association)	0.720
RNF14	DACH1	psi-mi:“MI:0915”(physical association)	0.720
UBE2D1	RNF14	psi-mi:“MI:0915”(physical association)	0.670
RNF14	UBE2D1	psi-mi:“MI:0915”(physical association)	0.670
GRN	RNF14	psi-mi:“MI:0915”(physical association)	0.560
PRKN	RNF14	psi-mi:“MI:0915”(physical association)	0.560
RNF11	RNF14	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	RNF14	psi-mi:“MI:0915”(physical association)	0.560
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
RNF14	AR	psi-mi:“MI:0914”(association)	0.500
RNF14	AR	psi-mi:“MI:0915”(physical association)	0.500
RNF14	HNF1A	psi-mi:“MI:0915”(physical association)	0.480
RNF14	HNF1A	psi-mi:“MI:0914”(association)	0.480

BioGRID (100): RNF14 (Two-hybrid), RNF14 (Two-hybrid), RNF14 (Two-hybrid), UBE2D4 (Two-hybrid), RNF14 (Affinity Capture-Western), RNF14 (Affinity Capture-MS), RNF14 (Affinity Capture-Western), PNPLA7 (Affinity Capture-Western), RNF14 (Affinity Capture-MS), AR (Two-hybrid), RNF14 (Reconstituted Complex), RNF14 (Reconstituted Complex), RNF14 (Two-hybrid), RNF14 (Two-hybrid), RNF14 (Two-hybrid)

ESM2 similar proteins: A9JTG5, B6DMK2, E0X9N4, F1RB95, O00463, O01965, O60678, O70467, O75417, O76924, O95376, P0C8K8, P39429, P70191, Q12933, Q14AI0, Q22431, Q4U5R4, Q5NU13, Q5XI55, Q5ZIJ9, Q5ZJM3, Q6GLD9, Q6J1I8, Q6J212, Q6J2U6, Q7Z569, Q84RR0, Q8CGS6, Q8L829, Q8VIL2, Q8W468, Q922H1, Q95K79, Q96BT7, Q96IV0, Q99MP8, Q9BVC3, Q9DFG8, Q9ERV1

Diamond homologs: A7YY45, A9UMG5, F1RB95, O13997, O55091, O60090, P32437, P32438, Q12257, Q54JW9, Q5GFD8, Q5GFD9, Q5M8G6, Q642J4, Q9P2X3, Q9UBS8, Q9W625, Q9XWF4, Q9JI90, A2A7Q9, A2VEA3, A4IIY1, B1H1E4, O01965, P0C8K8, P36113, P50636, Q08B84, Q1L8G6, Q1L8L6, Q2VJ60, Q32NS4, Q54CX4, Q6NW85, Q6PFJ9, Q6T486, Q6ZMZ0, Q6ZPS6, Q84RR0, Q8BKD6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF14	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	96.9×	1e-07
Antigen processing: Ubiquitination & Proteasome degradation	11	21.5×	5e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	6	90.4×	5e-09
protein monoubiquitination	6	79.4×	8e-09
protein K48-linked ubiquitination	8	51.9×	6e-10
protein K63-linked ubiquitination	5	51.4×	2e-06
protein polyubiquitination	8	35.5×	5e-09
ubiquitin-dependent protein catabolic process	7	20.0×	2e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	5	10.0×	4e-03
protein ubiquitination	5	8.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	42
Likely benign	5
Benign	7

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2022545	NM_016580.4(PCDH12):c.30del (p.Leu11fs)	Pathogenic
2690666	NM_016580.4(PCDH12):c.1082C>G (p.Ser361Ter)	Likely pathogenic
4081579	NM_016580.4(PCDH12):c.669del (p.Lys224fs)	Likely pathogenic

SpliceAI

1633 predictions. Top by Δscore:

Variant	Effect	Δscore
5:141973730:A:G	donor_gain	1.0000
5:141973736:G:GG	donor_gain	1.0000
5:141973738:GAGCG:G	donor_gain	1.0000
5:141973740:GCG:G	donor_gain	1.0000
5:141973743:G:GG	donor_gain	1.0000
5:141978390:G:GT	donor_gain	1.0000
5:141978594:G:GT	donor_gain	1.0000
5:141978624:A:G	donor_gain	1.0000
5:141980117:CTCCA:C	acceptor_loss	1.0000
5:141980120:CA:C	acceptor_loss	1.0000
5:141980121:AGGT:A	acceptor_loss	1.0000
5:141983378:A:AG	acceptor_gain	1.0000
5:141983379:G:GG	acceptor_gain	1.0000
5:141983379:GA:G	acceptor_gain	1.0000
5:141983379:GAGAA:G	acceptor_gain	1.0000
5:141973579:TCAG:T	acceptor_gain	0.9900
5:141973580:CAGG:C	acceptor_gain	0.9900
5:141973581:A:AG	acceptor_gain	0.9900
5:141973582:G:GA	acceptor_gain	0.9900
5:141973582:GGT:G	acceptor_gain	0.9900
5:141973582:GGTC:G	acceptor_gain	0.9900
5:141973582:GGTCC:G	acceptor_gain	0.9900
5:141973687:TG:T	donor_gain	0.9900
5:141973688:GG:G	donor_gain	0.9900
5:141973699:G:GT	donor_gain	0.9900
5:141973743:GTTA:G	donor_loss	0.9900
5:141973744:TTAG:T	donor_loss	0.9900
5:141973748:T:G	donor_gain	0.9900
5:141974796:T:TA	acceptor_gain	0.9900
5:141978301:A:AG	acceptor_gain	0.9900

AlphaMissense

3141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:141974938:T:A	W97R	0.999
5:141974938:T:C	W97R	0.999
5:141978372:T:A	W126R	0.998
5:141978372:T:C	W126R	0.998
5:141980294:T:C	F336L	0.998
5:141980296:C:A	F336L	0.998
5:141980296:C:G	F336L	0.998
5:141984902:T:C	F446L	0.998
5:141984904:C:A	F446L	0.998
5:141984904:C:G	F446L	0.998
5:141974873:T:C	L75P	0.997
5:141978366:T:C	F124L	0.997
5:141978368:T:A	F124L	0.997
5:141978368:T:G	F124L	0.997
5:141984823:G:C	K419N	0.997
5:141984823:G:T	K419N	0.997
5:141984857:T:A	W431R	0.997
5:141984857:T:C	W431R	0.997
5:141974896:T:C	Y83H	0.996
5:141974900:C:A	P84Q	0.996
5:141974915:C:A	P89H	0.996
5:141978654:T:C	C220R	0.996
5:141980213:T:C	C309R	0.996
5:141983526:T:C	C404R	0.996
5:141984813:G:A	G416E	0.996
5:141984825:T:C	M420T	0.996
5:141984830:T:C	C422R	0.996
5:141984831:G:A	C422Y	0.996
5:141984832:T:G	C422W	0.996
5:141984851:T:C	F429L	0.996

dbSNP variants (sampled 300 via entrez): RS1000035838 (5:141958479 C>T), RS1000042950 (5:141987336 G>A), RS1000153081 (5:141968374 G>A), RS1000195098 (5:141950448 T>A), RS1000221359 (5:141975310 C>G), RS1000242762 (5:141950696 G>A), RS1000552447 (5:141976850 A>G), RS1000606190 (5:141976532 CTT>C), RS1000646584 (5:141963527 T>C), RS1000675298 (5:141969123 G>C,T), RS1000687271 (5:141955494 A>C,G), RS1000697646 (5:141963841 A>G), RS1000706945 (5:141985275 T>C), RS1000755309 (5:141961369 C>T), RS1000901557 (5:141969742 T>C)

Disease associations

OMIM: gene MIM:605675 | disease phenotypes: MIM:251280

GenCC curated gene-disease

Mondo (3): diencephalic-mesencephalic junction dysplasia syndrome 1 (MONDO:0009625), diencephalic-mesencephalic junction dysplasia (MONDO:0017868), disorder of development or morphogenesis (MONDO:0021147)

Orphanet (1): Diencephalic-mesencephalic junction dysplasia (Orphanet:319192)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009213_3	Superior temporal gyrus volume	6.000000e-06
GCST009798_63	Asthma	9.000000e-14

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537546	Microcephaly with spastic quadriplegia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, decreases expression	2
Estradiol	affects expression, affects binding, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
quercitrin	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Bortezomib	increases expression	1
Decitabine	affects expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Quercetin	decreases expression	1

Clinical trials (associated diseases)

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