PPP1R13L

Summary

PPP1R13L (protein phosphatase 1 regulatory subunit 13 like, HGNC:18838) is a protein-coding gene on chromosome 19q13.32, encoding RelA-associated inhibitor (Q8WUF5). Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins.

IASPP is one of the most evolutionarily conserved inhibitors of p53 (TP53; MIM 191170), whereas ASPP1 (MIM 606455) and ASPP2 (MIM 602143) are activators of p53.

Source: NCBI Gene 10848 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arrhythmogenic cardiomyopathy with variable ectodermal abnormalities (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 217 total — 4 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_006663

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18838
Approved symbol	PPP1R13L
Name	protein phosphatase 1 regulatory subunit 13 like
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	RAI, IASPP
Ensembl gene	ENSG00000104881
Ensembl biotype	protein_coding
OMIM	607463
Entrez	10848

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 3 retained_intron

ENST00000360957, ENST00000418234, ENST00000585905, ENST00000587270, ENST00000589371, ENST00000589858, ENST00000591986, ENST00000592134, ENST00000593226, ENST00000863739, ENST00000863740, ENST00000863741, ENST00000863742, ENST00000863743, ENST00000863744

RefSeq mRNA: 2 — MANE Select: NM_006663 NM_001142502, NM_006663

CCDS: CCDS33050

Canonical transcript exons

ENST00000360957 — 13 exons

Exon	Start	End
ENSE00001399713	45391880	45392340
ENSE00001426671	45395436	45395886
ENSE00002860885	45404999	45405069
ENSE00003466046	45386049	45386180
ENSE00003508359	45398005	45398147
ENSE00003530864	45396338	45396436
ENSE00003547021	45382527	45382726
ENSE00003601632	45385562	45385728
ENSE00003617656	45379638	45380228
ENSE00003664455	45396168	45396259
ENSE00003672365	45396545	45397058
ENSE00003682281	45398264	45398339
ENSE00003692077	45385824	45385957

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1163 / max 368.6488, expressed in 1660 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181499	15.9273	1384
181501	4.7596	1516
181498	0.2168	130
181497	0.1594	80
181494	0.0530	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.21	gold quality
skin of abdomen	UBERON:0001416	98.76	gold quality
skin of leg	UBERON:0001511	98.64	gold quality
apex of heart	UBERON:0002098	98.57	gold quality
esophagus mucosa	UBERON:0002469	97.38	gold quality
zone of skin	UBERON:0000014	97.37	gold quality
cervix squamous epithelium	UBERON:0006922	96.57	silver quality
heart left ventricle	UBERON:0002084	96.46	gold quality
cardiac ventricle	UBERON:0002082	96.01	gold quality
right atrium auricular region	UBERON:0006631	96.00	gold quality
tongue squamous epithelium	UBERON:0006919	95.83	gold quality
right coronary artery	UBERON:0001625	95.59	gold quality
cardiac atrium	UBERON:0002081	95.08	gold quality
upper leg skin	UBERON:0004262	94.76	gold quality
ascending aorta	UBERON:0001496	94.72	gold quality
thoracic aorta	UBERON:0001515	94.50	gold quality
minor salivary gland	UBERON:0001830	94.34	gold quality
heart	UBERON:0000948	93.82	gold quality
mouth mucosa	UBERON:0003729	93.81	gold quality
aorta	UBERON:0000947	93.72	gold quality
upper arm skin	UBERON:0004263	93.67	gold quality
vagina	UBERON:0000996	93.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.46	gold quality
tibial artery	UBERON:0007610	93.40	gold quality
popliteal artery	UBERON:0002250	93.38	gold quality
descending thoracic aorta	UBERON:0002345	93.23	gold quality
gingival epithelium	UBERON:0001949	93.07	gold quality
left ventricle myocardium	UBERON:0006566	92.73	gold quality
saliva-secreting gland	UBERON:0001044	92.16	gold quality
esophagus	UBERON:0001043	91.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.64

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
BAX	Repression
TPM1

miRNA regulators (miRDB)

40 targeting PPP1R13L, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-606	98.72	67.34	960
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-1910-3P	98.44	67.51	1695

Literature-anchored findings (GeneRIF, showing 40)

• Effect of RAI on transcription and replication of human immunodeficiency virus type 1 (HIV-1). (PMID:12134007)
• The RAI protein, human is an evolutionarily conserved inhibitor of p53, and its expression is upregulated in human breast carcinomas expressing wild-type p53. (PMID:15607367)
• neither polymorphisms in several DNA repair genes nor alleles of several polymorphisms in the chromosomal of region 19q13.2-3, encompassing the genes ASE, ERCC1, RAI and XPD, were associated with risk of testicular cancer in Danish patients (PMID:15885892)
• role of ASPP1, ASPP2, and iASPP as apoptotic specific regulators of p53 [review] (PMID:16139958)
• The RAI polymorphism showed a trend towards risk reduction for both adenomas (OR of 0.70, 95% CI 0.49-1.01) and carcinomas (OR of 0.49, 95% CI 0.21-1.13) among wo (PMID:16817948)
• iASPP binds to and regulates the activity of p53 Pro72 variant more efficiently than that of p53 Arg72 (PMID:16964264)
• iASPP-SV is a nuclear protein, and is capable of binding to p53 in vivo. Overexpression of iASPP-SV can inhibit the transcriptional activity of p53 on the promoters of both Bax and p21. (PMID:17391696)
• RAI induction is necessary but not sufficient for apoptosis induction in non-transformed cells. (PMID:17570360)
• Data show here that RAI mRNA expression in human increased as gestation proceeded and that RAI was localized mainly in the syncytiotrophoblast throughout pregnancy. (PMID:17872376)
• Data suggest that Pin1 is required for efficient loading of p53 on target promoters upon stress, and that after phosphorylation of p53 triggered by cytotoxic stimuli, Pin1 mediates p53’s dissociation from iASPP, promoting cell death. (PMID:17906639)
• 3-dimensional structure of RelA-associated inhibitor in complex with p53 using computational chemistry. (PMID:18201273)
• High-resolution crystal structure for the C terminus of iASPP, comprised of four ankyrin repeats and an SH3 domain. (PMID:18275817)
• No consistent association between RAI polymorphism, the haplotype and risk of colorectal cancer has been found. (PMID:18289367)
• We expect the marker RAI-3’d1 to be (part of) the cause for the association of the chromosome 19q13.3 region’s association with cancer (PMID:18588689)
• Inhibition of expression of iASPP may resume the ability of p53 to induce apoptosis in MCF-7 cells. (PMID:18798069)
• ASPP2 primarily binds to the core domain of p53, whereas iASPP predominantly interacts with a linker region adjacent to the core domain. (PMID:19246451)
• results suggest that polymorphism Asn118Asn in ERCC1, A67T in iASPP and Asn148Glu in APE1 may associated with early onset of lung cancer as well as some specific subtype of lung cancer (PMID:20354815)
• Single-nucleotide polymorphisms in PPP1R13L gene is associated with early-stage non-small-cell lung cancer. (PMID:20422457)
• iASPP is up-regulated in hepatocellular carcinoma; it is a direct transcription target of NF-kappaB (PMID:20600029)
• Data provide evidence that endogenous PPP1R13L acts as a negative regulator of p53 function, presumably by direct binding. (PMID:20840860)
• Role of iASPP in cell cycle progression of glioblastoma cells. (PMID:21184255)
• iASPP regulates the proliferation and motility of lung cancer cells. This effect is intimately associated with the p53 pathway. (PMID:21192816)
• results showed that iASPP mRNA and protein levels were significantly down-regulated in both cells infected with the siRNA against iASPP (PMID:21391736)
• iASPP is essential for prostate cancer cellular proliferation and survival and may be a potential target for the gene therapy for prostate cancer (PMID:21625267)
• These data showed iASPP to be a key regulator of epithelial homeostasis in skin. (PMID:21897369)
• Data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. (PMID:21926165)
• Study identifies iASPP as a new binding partner of PP1, interacting through a noncanonical PP1 binding motif. (PMID:21998301)
• variant alleles of PPP1R13L rs1970764 and CD3EAP rs967591 may contribute to risk factors of lung cancer. (PMID:22335888)
• Highly significant differential distributions of haplotypes defined by both nine haplotype-tagging SNPs covering ERCC2 and PPP1R13L and fourteen haplotype-tagging SNPs covering ERCC2, PPP1R13L, and ERCC1 were found. (PMID:22351191)
• iASPP inhibited apoptosis independently of p53 in tumor cells, mainly by inhibiting the transcriptional activity of p63/p73 on the promoters of proapoptotic genes (PMID:22538442)
• Downregulation of iASPP by siRNA stimulated apoptosis through p53 in two non-small cell lung cancer cell lines (PMID:22552744)
• These findings showed that iAPSS/iASPPsv reduced the growth inhibition and apoptosis induced by Dex or VP-16, with DNA damage accumulating which might promote the pathogenesis and/or progression of cancer. (PMID:22766503)
• results suggest iASPP may contribute to the malignant progression of head and neck squamous cell carcinoma (PMID:22815155)
• When the Px(T)PxR motif is deleted or mutated via insertion of a phosphorylation site mimic (T311D), PP-1c fails to bind to all three ASPP proteins, ASPP1, ASPP2 and iASPP. (PMID:23088536)
• The PPP1R13L rs1970764 variant is a possible prognostic marker for patients with rectal cancer. (PMID:23180017)
• This study thus demonstrates that iASPP is highly elevated in human cervical cancer, and that overexpression of nuclear iASPP is correlated with poor prognosis and chemoresistance/radioresistance (PMID:23420450)
• higher rate Helicobacter pylori infection, an increased expression of inhibitor of apoptosis stimulating protein of p53 (iASPP), and decreased expression of apoptosis-stimulating of p53 protein 2(ASPP2) was present in gastric cancer (PMID:23528480)
• PPP1R13L and CD3EAP variants may be associated with lung cancer risk in nonsmoking Chinese women. (PMID:23624123)
• Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L. (PMID:23624869)
• Haplotype PPP1R13L rs4803817 polymorphism is associated with lung cancer risk. (PMID:24140460)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r13l	ENSDARG00000013777
mus_musculus	Ppp1r13l	ENSMUSG00000040734
rattus_norvegicus	Ppp1r13l	ENSRNOG00000025350
caenorhabditis_elegans		WBGENE00007877

Protein

Protein identifiers

RelA-associated inhibitor — Q8WUF5 (reviewed: Q8WUF5)

Alternative names: Inhibitor of ASPP protein, NFkB-interacting protein 1, PPP1R13B-like protein

All UniProt accessions (5): Q8WUF5, K7EML6, K7EN03, K7ENG6, K7EPP1

UniProt curated annotations — full annotation on UniProt →

Function. Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins. Blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. Also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis. Is involved in NF-kappa-B dependent negative regulation of inflammatory response.

Subunit / interactions. Interacts with RELA NF-kappa-B subunit and with SP1 via its C-terminus part. Interacts (via SH3 domain and ANK repeats) with p53/TP53; the interaction inhibits pro-apoptotic activity of p53/TP53. Interacts with TP63 and TP73.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in heart, placenta and prostate. Weakly expressed in brain, liver, skeletal muscle, testis and peripheral blood leukocyte.

Disease relevance. Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities (ARCME) [MIM:620519] An autosomal recessive disorder characterized by life-threatening dilated cardiomyopathy in early childhood, with or without features of inflammation on cardiac histology. There is also a variably expressed ectodermal phenotype, including wooly or wiry hair, wedged teeth, xerotic skin, and dystrophic nails. Cleft lip and palate and corneal abnormalities have also been observed. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal region is required for cytoplasmic localization. The ANK repeats and the SH3 domain are required for specific interactions with p53/TP53.

Similarity. Belongs to the iASPP family.

RefSeq proteins (2): NP_001135974, NP_006654* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR028320	iASPP	Family
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR042722	SH3_iASPP	Domain

Pfam: PF12796, PF14604

UniProt features (74 total): modified residue 29, helix 10, sequence conflict 9, compositionally biased region 6, sequence variant 5, strand 5, region of interest 4, repeat 2, turn 2, chain 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6HL6	X-RAY DIFFRACTION	1.97
2VGE	X-RAY DIFFRACTION	2.1
9GFO	X-RAY DIFFRACTION	2.4
6DCX	X-RAY DIFFRACTION	3.41
6RZ3	X-RAY DIFFRACTION	4.23

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WUF5-F1	57.52	0.24

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 (29): 1, 84, 100, 102, 110, 113, 119, 120, 123, 134, 137, 142, 144, 160, 167, 180, 183, 187, 203, 205 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6804759	Regulation of TP53 Activity through Association with Co-factors

MSigDB gene sets: 249 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_GROWTH, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_VENTRICULAR_CARDIAC_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_HEART_MORPHOGENESIS, GOBP_CARDIAC_VENTRICLE_MORPHOGENESIS, GOBP_CARDIAC_RIGHT_VENTRICLE_MORPHOGENESIS

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), cardiac right ventricle morphogenesis (GO:0003215), ventricular cardiac muscle tissue development (GO:0003229), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), post-embryonic development (GO:0009791), embryonic camera-type eye development (GO:0031076), multicellular organism growth (GO:0035264), hair cycle (GO:0042633), positive regulation of cell differentiation (GO:0045597), multicellular organismal-level homeostasis (GO:0048871), negative regulation of inflammatory response (GO:0050728), cardiac muscle contraction (GO:0060048), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): transcription corepressor activity (GO:0003714), identical protein binding (GO:0042802), cadherin binding (GO:0045296), protein binding (GO:0005515), transcription factor binding (GO:0008134)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), cell junction (GO:0030054), intercellular bridge (GO:0045171), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of TP53 Activity	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
multicellular organismal process	3
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
protein binding	2
regulation of transcription by RNA polymerase II	1
cardiac ventricle morphogenesis	1
cardiac muscle tissue development	1
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
multicellular organism development	1
camera-type eye development	1
embryonic organ development	1
developmental growth	1
molting cycle	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
homeostatic process	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
striated muscle contraction	1
heart contraction	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription coregulator activity	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R13L	TP53	P04637	910
PPP1R13L	CDK1	P06493	845
PPP1R13L	RELA	Q04206	845
PPP1R13L	POLR1G	O15446	657
PPP1R13L	MDM2	Q00987	623
PPP1R13L	KEAP1	Q14145	589
PPP1R13L	BCL2	P10415	569
PPP1R13L	ERCC2	P18074	567
PPP1R13L	CASP3	P42574	487
PPP1R13L	DSP	P15924	467
PPP1R13L	TP53BP2	Q13625	465
PPP1R13L	AURKA	O14965	456
PPP1R13L	CDK2	P24941	446
PPP1R13L	TP73	O15350	407
PPP1R13L	NFATC1	O95644	402

IntAct

241 interactions, top by confidence:

A	B	Type	Score
PPP1CA	PPP1R13L	psi-mi:“MI:0915”(physical association)	0.930
MAPRE1	CLASP2	psi-mi:“MI:0914”(association)	0.850
PPP1R13L	TP53	psi-mi:“MI:0407”(direct interaction)	0.810
PPP1R13L	TP53	psi-mi:“MI:0915”(physical association)	0.810
TP53	PPP1R13L	psi-mi:“MI:0915”(physical association)	0.810
PPP1R13L	TP53	psi-mi:“MI:0403”(colocalization)	0.810
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
DCAF7	DIAPH1	psi-mi:“MI:0914”(association)	0.730
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
PPP1R13L	PPP1R13L	psi-mi:“MI:0407”(direct interaction)	0.680
PPP1R13L	PPP1R13L	psi-mi:“MI:0915”(physical association)	0.680

BioGRID (170): TP53 (Affinity Capture-Western), PPP1R13L (Affinity Capture-Western), EP300 (Affinity Capture-Western), TP53 (Affinity Capture-Western), TP53 (Affinity Capture-Western), PPP1R13L (Two-hybrid), PPP1R13L (Affinity Capture-MS), PPP1R13L (Affinity Capture-MS), PPP1R13L (Affinity Capture-MS), PPP1R13L (Affinity Capture-MS), PPP1R13L (Affinity Capture-MS), CREBBP (Affinity Capture-Western), EP300 (Affinity Capture-Western), PPP1R13L (Affinity Capture-Western), PPP1R13L (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RR37, A1L170, A1L1I3, A1L260, A2AMM0, A4IFJ0, B5G1P1, D3ZQL6, E7F5E1, G5BQH4, O08919, O54724, O60237, O75420, P06759, P33622, P53814, P85125, Q2KI85, Q2TAL5, Q3T044, Q3UMT1, Q4RTJ5, Q4V882, Q5I1X5, Q5U2R6, Q63312, Q6NZI2, Q75AS0, Q80VC9, Q8BG95, Q8BGT6, Q8C0J6, Q8CI12, Q8IV56, Q8K382, Q8N3F8, Q8TEH3, Q8WUF5, Q91VJ2

Diamond homologs: A0A8I3PDQ1, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, O13736, O35177, O35179, O35964, O42287, O43281, P29355, P34109, P38753, P43603, P56945, Q08012, Q0CJU8, Q0P5B1, Q0U6X7, Q14511, Q15811, Q16584, Q1E878, Q2GT05, Q4R729, Q4WHP5, Q557J6, Q5BBL4, Q5I1X5, Q61140, Q62419, Q62420, Q63767, Q64355, Q66HA1, Q6BNP6, Q6C2N2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CDK1	“up-regulates activity”	PPP1R13L	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 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
Ras activation upon Ca2+ influx through NMDA receptor	5	31.0×	7e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	29.6×	7e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	29.6×	7e-05
Long-term potentiation	5	25.9×	1e-04
Assembly and cell surface presentation of NMDA receptors	9	24.8×	4e-08
Neurexins and neuroligins	9	19.3×	2e-07
Protein-protein interactions at synapses	5	14.4×	2e-03
RHOQ GTPase cycle	5	9.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	38.2×	1e-09
protein localization to synapse	5	28.0×	2e-04
receptor clustering	5	22.8×	6e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	5	18.1×	1e-03
protein-containing complex assembly	11	9.1×	2e-05
exocytosis	8	8.9×	7e-04
cell-cell adhesion	9	6.7×	1e-03
protein transport	12	3.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	8
Uncertain significance	142
Likely benign	33
Benign	11

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1188825	NM_006663.4(PPP1R13L):c.580C>T (p.Gln194Ter)	Pathogenic
1699017	NM_006663.4(PPP1R13L):c.1068dup (p.Ser357fs)	Pathogenic
4083450	NM_006663.4(PPP1R13L):c.1366_1367delinsA (p.Pro456fs)	Pathogenic
427813	NM_006663.4(PPP1R13L):c.2241C>G (p.Tyr747Ter)	Pathogenic
3781340	NM_006663.4(PPP1R13L):c.287del (p.Pro96fs)	Likely pathogenic
4072284	NM_006663.4(PPP1R13L):c.1668del (p.Pro557fs)	Likely pathogenic
4537416	NM_006663.4(PPP1R13L):c.1915G>A (p.Glu639Lys)	Likely pathogenic
4849470	NM_006663.4(PPP1R13L):c.893dup (p.Thr299fs)	Likely pathogenic
974803	NM_006663.4(PPP1R13L):c.2486_2487delinsTC (p.Ter829Phe)	Likely pathogenic
974804	NM_006663.4(PPP1R13L):c.1610del (p.Pro537fs)	Likely pathogenic
974807	NM_006663.4(PPP1R13L):c.1537del (p.Val513fs)	Likely pathogenic
974808	NM_006663.4(PPP1R13L):c.1219C>T (p.Gln407Ter)	Likely pathogenic

SpliceAI

1889 predictions. Top by Δscore:

Variant	Effect	Δscore
19:45382515:C:A	donor_gain	1.0000
19:45382525:AC:A	donor_gain	1.0000
19:45382526:CC:C	donor_gain	1.0000
19:45382724:CGT:C	acceptor_gain	1.0000
19:45382727:C:CC	acceptor_gain	1.0000
19:45382734:A:C	acceptor_gain	1.0000
19:45385558:GCACC:G	donor_loss	1.0000
19:45385559:CA:C	donor_loss	1.0000
19:45385560:A:T	donor_loss	1.0000
19:45385561:C:CA	donor_loss	1.0000
19:45385613:T:TA	donor_gain	1.0000
19:45385734:C:CT	acceptor_gain	1.0000
19:45385735:G:C	acceptor_gain	1.0000
19:45385822:A:AC	donor_gain	1.0000
19:45385823:C:CC	donor_gain	1.0000
19:45385953:TTCAT:T	acceptor_gain	1.0000
19:45385954:TCAT:T	acceptor_gain	1.0000
19:45385955:CAT:C	acceptor_gain	1.0000
19:45385955:CATC:C	acceptor_gain	1.0000
19:45385956:ATC:A	acceptor_loss	1.0000
19:45385957:TCT:T	acceptor_loss	1.0000
19:45385958:C:CC	acceptor_gain	1.0000
19:45385958:CT:C	acceptor_loss	1.0000
19:45385959:T:A	acceptor_loss	1.0000
19:45385962:G:C	acceptor_gain	1.0000
19:45385962:G:GC	acceptor_gain	1.0000
19:45385965:C:CT	acceptor_gain	1.0000
19:45385968:C:CT	acceptor_gain	1.0000
19:45385968:C:T	acceptor_gain	1.0000
19:45385969:G:T	acceptor_gain	1.0000

AlphaMissense

5317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:45382639:A:G	F779S	1.000
19:45385578:G:C	C744W	1.000
19:45385579:C:T	C744Y	1.000
19:45385608:G:C	C734W	1.000
19:45385609:C:G	C734S	1.000
19:45385609:C:T	C734Y	1.000
19:45385610:A:G	C734R	1.000
19:45385610:A:T	C734S	1.000
19:45385675:A:G	L712P	1.000
19:45385683:G:C	C709W	1.000
19:45385684:C:T	C709Y	1.000
19:45385685:A:G	C709R	1.000
19:45385698:G:C	N704K	1.000
19:45385698:G:T	N704K	1.000
19:45385699:T:A	N704I	1.000
19:45385702:C:T	C703Y	1.000
19:45385713:G:C	C699W	1.000
19:45385714:C:G	C699S	1.000
19:45385714:C:T	C699Y	1.000
19:45385715:A:G	C699R	1.000
19:45385715:A:T	C699S	1.000
19:45385723:G:C	P696R	1.000
19:45385723:G:T	P696H	1.000
19:45385728:C:A	W694C	1.000
19:45385728:C:G	W694C	1.000
19:45385825:A:G	W694R	1.000
19:45385825:A:T	W694R	1.000
19:45385836:T:A	D690V	1.000
19:45385869:A:G	L679P	1.000
19:45385869:A:T	L679H	1.000

dbSNP variants (sampled 300 via entrez): RS1000013382 (19:45397095 G>T), RS1000299632 (19:45380875 A>C,G), RS1000456311 (19:45393224 A>C,G), RS1000488749 (19:45393094 A>C,G), RS1000613135 (19:45394497 T>C), RS1000664195 (19:45387972 C>T), RS1000812860 (19:45387607 T>C), RS1000892061 (19:45404731 C>A), RS1000972415 (19:45390744 G>A), RS1001039735 (19:45406114 G>T), RS1001051771 (19:45398377 G>A,C,T), RS1001182768 (19:45387752 C>T), RS1001363703 (19:45403137 G>A), RS1001425478 (19:45398791 C>T), RS1001545568 (19:45382100 G>A)

Disease associations

OMIM: gene MIM:607463 | disease phenotypes: MIM:620519, MIM:119530

GenCC curated gene-disease

Disease	Classification	Inheritance
arrhythmogenic cardiomyopathy with variable ectodermal abnormalities	Definitive	Autosomal recessive
dilated cardiomyopathy	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
arrhythmogenic cardiomyopathy with variable ectodermal abnormalities	Definitive	AR

Mondo (4): arrhythmogenic cardiomyopathy with variable ectodermal abnormalities (MONDO:0957795), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), dilated cardiomyopathy (MONDO:0005021), orofacial cleft (MONDO:0000358)

Orphanet (2): Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), Dilated cardiomyopathy (Orphanet:217604)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001249	Intellectual disability
HP:0001270	Motor delay
HP:0001508	Failure to thrive
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001644	Dilated cardiomyopathy
HP:0001647	Bicuspid aortic valve
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale
HP:0001685	Myocardial fibrosis
HP:0001698	Pericardial effusion
HP:0001806	Onycholysis
HP:0002208	Coarse hair
HP:0002209	Sparse scalp hair
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004756	Ventricular tachycardia
HP:0005180	Tricuspid regurgitation
HP:0005280	Depressed nasal bridge
HP:0007957	Corneal opacity
HP:0008064	Ichthyosis
HP:0008404	Nail dystrophy
HP:0009890	High anterior hairline
HP:0011359	Dry hair
HP:0011463	Childhood onset
HP:0012413	Notched primary central incisor
HP:0025169	Left ventricular systolic dysfunction

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-97
GCST90000015_25	Parkinson’s disease motor subtype (tremor to postural instability/gait difficulty score ratio)	8.000000e-06
GCST90002402_568	Platelet count	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0600011	Parkinson’s disease symptom measurement
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3212986	Efficacy	3	Platinum compounds	Ovarian Neoplasms
rs3212986	Efficacy	3	cisplatin;gemcitabine	Mesothelioma
rs3212986	Toxicity	3	doxorubicin	Infectious disease;Leukopenia;Osteosarcoma

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs735482	ERCC1, POLR1G, PPP1R13L	3	2.00	1	thalidomide
rs967591	POLR1G, PPP1R13L		0.00	0
rs3212986	ERCC1, POLR1G, PPP1R13L	3	4.00	11	cisplatin;Platinum compounds;docetaxel;paclitaxel;cisplatin;gemcitabine;bleomycin;cisplatin;etoposide;cyclophosphamide;doxorubicin;fluorouracil;granisetron;palonosetron;doxorubicin
rs4572514	POLR1G, PPP1R13L		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	5
trichostatin A	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Etoposide	increases expression, increases localization, decreases response to substance	2
Quercetin	increases expression, decreases phosphorylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases methylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	increases expression	1
Caffeine	affects phosphorylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2BT	Abcam HeLa PPP1R13L KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	PHASE2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	PHASE2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	PHASE2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	PHASE2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	PHASE2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM
NCT03775070	PHASE2	COMPLETED	Simvastatin Therapy in Patients With Dilated Cardiomyopathy.
NCT04405804	PHASE2	UNKNOWN	Early Administration of Ivabradine in Children With Heart Failure
NCT05410873	PHASE2	COMPLETED	Examining the Effects of Mitochondrial Oxidative Stress in DCM
NCT06632834	PHASE2	RECRUITING	Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation
NCT00585546	PHASE1	TERMINATED	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
NCT02293603	PHASE1	UNKNOWN	Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC)
NCT03062956	PHASE1	COMPLETED	A Single Ascending Dose Study Assessing the Safety, Tolerability, PK and PD of MYK-491
NCT03129568	PHASE1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Pediatric Dilated Cardiomyopathy
NCT04982081	PHASE1	UNKNOWN	Treating Congestive HF With hiPSC-CMs Through Endocardial Injection
NCT06381466	PHASE1	TERMINATED	A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.
NCT06464588	PHASE1	RECRUITING	A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
NCT06902896	PHASE1	COMPLETED	Safety and Efficacy of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT07137338	PHASE1	RECRUITING	A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy
NCT07241104	PHASE1	RECRUITING	A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy