TRAIP

Summary

TRAIP (TRAF interacting protein, HGNC:30764) is a protein-coding gene on chromosome 3p21.31, encoding E3 ubiquitin-protein ligase TRAIP (Q9BWF2). E3 ubiquitin ligase required to protect genome stability in response to replication stress. It is a selective cancer dependency (DepMap: 81.7% of cell lines).

This gene encodes a protein that contains an N-terminal RING finger motif and a putative coiled-coil domain. A similar murine protein interacts with TNFR-associated factor 1 (TRAF1), TNFR-associated factor 2 (TRAF2), and cylindromatosis. The interaction with TRAF2 inhibits TRAF2-mediated nuclear factor kappa-B, subunit 1 activation that is required for cell activation and protection against apoptosis.

Source: NCBI Gene 10293 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Seckel syndrome 9 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 232 total — 12 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 50
• Cancer dependency (DepMap): dependent in 81.7% of screened cell lines
• MANE Select transcript: NM_005879

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30764
Approved symbol	TRAIP
Name	TRAF interacting protein
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	TRIP, RNF206
Ensembl gene	ENSG00000183763
Ensembl biotype	protein_coding
OMIM	605958
Entrez	10293

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 17 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000331456, ENST00000469027, ENST00000473195, ENST00000473863, ENST00000475495, ENST00000477546, ENST00000482243, ENST00000482582, ENST00000488860, ENST00000489948, ENST00000491060, ENST00000891847, ENST00000891848, ENST00000929617, ENST00000929618, ENST00000929619, ENST00000929620, ENST00000929621, ENST00000929622, ENST00000929623, ENST00000929624, ENST00000929625, ENST00000967097, ENST00000967098

RefSeq mRNA: 1 — MANE Select: NM_005879 NM_005879

CCDS: CCDS2806

Canonical transcript exons

ENST00000331456 — 15 exons

Exon	Start	End
ENSE00001290242	49843801	49843928
ENSE00001291230	49841826	49841939
ENSE00001299748	49828601	49829225
ENSE00001309633	49842453	49842547
ENSE00001329595	49840985	49841072
ENSE00003471351	49829458	49829508
ENSE00003492851	49847525	49847608
ENSE00003514428	49840284	49840373
ENSE00003520695	49839772	49839860
ENSE00003547640	49856356	49856564
ENSE00003560221	49829617	49829766
ENSE00003613665	49844541	49844580
ENSE00003623604	49831916	49832068
ENSE00003657283	49848143	49848200
ENSE00003680642	49830020	49830068

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 88.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.3264 / max 91.0908, expressed in 1365 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42282	4.9886	1351
42281	0.3378	186

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.60	gold quality
ventricular zone	UBERON:0003053	84.85	gold quality
ganglionic eminence	UBERON:0004023	82.20	gold quality
mucosa of transverse colon	UBERON:0004991	80.38	gold quality
left testis	UBERON:0004533	79.63	gold quality
right testis	UBERON:0004534	79.15	gold quality
endometrium epithelium	UBERON:0004811	77.99	silver quality
testis	UBERON:0000473	77.30	gold quality
lower esophagus mucosa	UBERON:0035834	76.45	gold quality
stromal cell of endometrium	CL:0002255	75.68	gold quality
rectum	UBERON:0001052	75.37	gold quality
nucleus accumbens	UBERON:0001882	75.34	gold quality
right uterine tube	UBERON:0001302	74.75	gold quality
esophagus mucosa	UBERON:0002469	73.88	gold quality
embryo	UBERON:0000922	73.67	gold quality
cortical plate	UBERON:0005343	73.62	gold quality
granulocyte	CL:0000094	72.90	gold quality
skin of leg	UBERON:0001511	72.65	gold quality
skin of abdomen	UBERON:0001416	72.21	gold quality
ectocervix	UBERON:0012249	72.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.92	gold quality
lymph node	UBERON:0000029	71.06	gold quality
body of uterus	UBERON:0009853	71.06	gold quality
transverse colon	UBERON:0001157	71.02	gold quality
adrenal tissue	UBERON:0018303	70.96	gold quality
calcaneal tendon	UBERON:0003701	70.86	gold quality
left ovary	UBERON:0002119	70.82	gold quality
right ovary	UBERON:0002118	70.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting TRAIP, 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-4775	99.98	75.00	6394
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
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-5001-5P	99.05	66.76	1972
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-6811-5P	97.98	64.96	848
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6769B-3P	97.41	65.53	1036
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-4433B-3P	97.22	63.62	663
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-4281	92.91	63.60	271

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 81.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 26)

• CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. (PMID:14676304)
• The overexpression of TRIP sensitizes cells to TNF-induced apoptosis, an effect that can be reversed by the coexpression of Syk. (PMID:19151749)
• The TRAF-interacting protein (TRIP) is a regulator of keratinocyte proliferation. (PMID:21068752)
• observed enhanced ubiquitylation of Poleta by TRIP E3 ligase and show that TRIP promotes Poleta localization to nuclear foci (PMID:24553286)
• The TRAIP ubiquitin ligase activity is functionally required for the spindle assembly checkpoint control. (PMID:25335891)
• Data indicate that TRAF interacting protein TRIP negatively regulates the TNFR-associated factor 2 (TRAF2) ubiquitin-dependent pathway by modulating the TRAF2-sphingosine 1-phosphate (S1P) interaction. (PMID:25716317)
• a number of TRAIP mutants were used to define the TRAIP molecular domains responsible for its homo-dimerization. A co-immunoprecipitation assay indicated that the TRAIP forms homo-dimerization through the CC domain (PMID:26093298)
• cell cycle-dependent transcription of the TRAIP gene by E2F1, E2F2, and E2F4 and rapid protein degradation leads to cell cycle-dependent expression with a maximum in G2/M (PMID:26369285)
• TRAIP is a component of the DNA damage response to replication-blocking DNA lesions.TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. (PMID:26595769)
• These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication. (PMID:26711499)
• TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage.( (PMID:26781088)
• Taken together, these findings improve the understanding clinical implication of TRAIP in various diseases including primordial dwarfism and cancers. (PMID:26820530)
• TRIP interacts with transforming growth factor beta-activated kinase 1 (TAK1) and promotes K48-linked polyubiquitination of TAK1 in rheumatoid arthritis fibroblast-Like synoviocytes (PMID:27847407)
• The TRAIP coiled-coil domain altered its stoichiometry between dimer and trimer in a concentration-dependent manner. Additionally, the TRAIP RING domain induced even higher-ordered assembly, which was necessary for interacting with the TRAF-N domain of TRAF2 but not TRAF1. (PMID:30127245)
• Nucleolar residence of the Seckel syndrome protein TRAIP is coupled to ribosomal DNA transcription. (PMID:30165463)
• present results, together with other recent findings, establish TRAIP as a master regulator of DNA helicase CMG unloading and the response of the replisome to obstacles (PMID:30842657)
• hese results suggest that TRAIP is a novel regulator of H2B monoubiquitination in DNA damage response and cancer development in lung adenocarcinoma. (PMID:30942468)
• TRAIP promotes malignant behaviors and correlates with poor prognosis in liver cancer. (PMID:31972358)
• TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. (PMID:31980815)
• TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1. (PMID:32640040)
• The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome. (PMID:33317933)
• TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. (PMID:34349117)
• Silencing TRAIP suppresses cell proliferation and migration/invasion of triple negative breast cancer via RB-E2F signaling and EMT. (PMID:36064576)
• ZNF212 promotes genomic integrity through direct interaction with TRAIP. (PMID:36594163)
• TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells. (PMID:37604812)
• TRAIP suppressed apoptosis and cell cycle to promote prostate cancer proliferation via TRAF2-PI3K-AKT pathway activation. (PMID:38100027)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	traip	ENSDARG00000011262
mus_musculus	Traip	ENSMUSG00000032586
rattus_norvegicus	Traip	ENSRNOG00000030101

Protein

Protein identifiers

E3 ubiquitin-protein ligase TRAIP — Q9BWF2 (reviewed: Q9BWF2)

Alternative names: RING finger protein 206, TRAF-interacting protein

All UniProt accessions (5): E7EN91, E7ETV1, E7EVC4, E7EW89, Q9BWF2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase required to protect genome stability in response to replication stress. Acts as a key regulator of interstrand cross-link repair, which takes place when both strands of duplex DNA are covalently tethered together, thereby blocking replication and transcription. Controls the choice between the two pathways of replication-coupled interstrand-cross-link repair by mediating ubiquitination of MCM7 subunit of the CMG helicase complex. Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3. If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase, enabling the Fanconi anemia DNA repair pathway. Only catalyzes ubiquitination of MCM7 when forks converge. Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: promotes ubiquitination of DPCs, leading to their degradation by the proteasome. Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of ‘Lys-63’-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity. The function in translesion synthesis is however controversial. Acts as a regulator of the spindle assembly checkpoint. Also acts as a negative regulator of innate immune signaling by inhibiting activation of NF-kappa-B mediated by TNF. Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting ‘Lys-48’-linked polyubiquitination of TNK1 leading to its proteasomal degradation.

Subunit / interactions. Interacts (via PIP-box) with PCNA. Binds TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 is part of the receptor-TRAF signaling complex. May interact with CYLD; the C-terminus interacts with CYLD, however the interaction was not detected with the full-length protein. Interacts with POLK and POLN. Interacts with UIMC1.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Chromosome. Cytoplasm. Perinuclear region.

Post-translational modifications. Sumoylated; sumoylation is required for nuclear localization. Sumoylation increases protein stability, possibly by preventing ubiquitination. Autoubiquitinated.

Disease relevance. Seckel syndrome 9 (SCKL9) [MIM:616777] A form of Seckel syndrome, a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TRAIP family.

RefSeq proteins (1): NP_005870* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR052639	TRAIP_ubiq-protein_ligase	Family

Pfam: PF13639

UniProt features (22 total): mutagenesis site 9, sequence conflict 4, coiled-coil region 2, chain 1, zinc finger region 1, region of interest 1, helix 1, short sequence motif 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4ZTD	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BWF2-F1	75.24	0.48

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 (1): 304

Mutagenesis-validated functional residues (9):

Position	Phenotype
80	abolished sumoylation and localization to the nucleus; when associated with a-127, a-205, a-247 and a-462.
127	abolished sumoylation and localization to the nucleus; when associated with a-80, a-205, a-247 and a-462.
205	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-247 and a-462.
247	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-205 and a-462.
460–463	abolished interaction with pcna and localization to dna damage sites.
462	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-205 and a-247.
466	abolished interaction with pcna.
7	abolished accumulation in nucleolus.
25	abolished ability to regulate nuclear envelope breakdown to anaphase.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 297 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, CROONQUIST_NRAS_SIGNALING_DN, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, PATIL_LIVER_CANCER, MUELLER_PLURINET, CAGCAGG_MIR370, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MODULE_205, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (9): apoptotic process (GO:0006915), DNA damage response (GO:0006974), signal transduction (GO:0007165), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), protein ubiquitination (GO:0016567), replication fork processing (GO:0031297), negative regulation of interferon-beta production (GO:0032688), protein-DNA covalent cross-linking repair (GO:0106300), DNA repair (GO:0006281)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), perinuclear region of cytoplasm (GO:0048471), site of DNA damage (GO:0090734), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclear lumen	2
intracellular membraneless organelle	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
protein modification by small protein conjugation	1
DNA-templated DNA replication maintenance of fidelity	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
DNA repair	1
DNA metabolic process	1
DNA damage response	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
chromosome	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1144 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAIP	CYLD	Q9NQC7	837
TRAIP	TRAF1	Q13077	791
TRAIP	NEIL3	Q8TAT5	666
TRAIP	SPRTN	Q9H040	662
TRAIP	LRR1	Q96L50	647
TRAIP	UIMC1	Q96RL1	577
TRAIP	TRADD	Q15628	573
TRAIP	MCM7	P33993	567
TRAIP	FANCD2	Q9BXW9	561
TRAIP	TNFRSF8	P28908	560
TRAIP	CDC45	O75419	556
TRAIP	TANK	Q92844	523
TRAIP	TNFRSF1B	P20333	506
TRAIP	SLX4	Q8IY92	504
TRAIP	RNF20	Q5VTR2	502

IntAct

57 interactions, top by confidence:

A	B	Type	Score
TRAIP	MAPRE2	psi-mi:“MI:0915”(physical association)	0.780
MAPRE2	TRAIP	psi-mi:“MI:0915”(physical association)	0.780
LXN	TRAIP	psi-mi:“MI:0915”(physical association)	0.560
TRAIP	TRAIP	psi-mi:“MI:0915”(physical association)	0.560
CEP19	TRAIP	psi-mi:“MI:0915”(physical association)	0.560
ALOX15B	TRAIP	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	TRAIP	psi-mi:“MI:0915”(physical association)	0.560
TRAIP	MAPRE3	psi-mi:“MI:0915”(physical association)	0.560
TRAIP		psi-mi:“MI:0915”(physical association)	0.560
TRAIP	UBE2K	psi-mi:“MI:0915”(physical association)	0.560
TRAIP	JPH3	psi-mi:“MI:0915”(physical association)	0.560
TRAIP	FYN	psi-mi:“MI:0915”(physical association)	0.400
TRAIP	GRB2	psi-mi:“MI:0915”(physical association)	0.400
NCK1	TRAIP	psi-mi:“MI:0915”(physical association)	0.400
PLCG1	TRAIP	psi-mi:“MI:0915”(physical association)	0.400
UBE2U	TRAIP	psi-mi:“MI:0915”(physical association)	0.370
TRAIP	TSG101	psi-mi:“MI:0915”(physical association)	0.370
HIP2	TRAIP	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (111): MAPRE2 (Two-hybrid), TRAIP (Affinity Capture-Western), TRAIP (Affinity Capture-Western), TRAIP (Reconstituted Complex), TRAIP (Affinity Capture-Western), TRAIP (Reconstituted Complex), TRAIP (Co-crystal Structure), TRAIP (Two-hybrid), FLII (Two-hybrid), MAP3K7 (Affinity Capture-Western), UIMC1 (Two-hybrid), UIMC1 (Affinity Capture-Western), TRAIP (Affinity Capture-Western), TRAIP (Affinity Capture-Western), TRAIP (Affinity Capture-Western)

ESM2 similar proteins: A2Y040, D3ZVU1, E1BC52, G3X912, O15304, O43900, O54880, O54926, O73916, P59692, P86346, Q08AE8, Q0IH40, Q0VCH3, Q0VDN7, Q1LXR6, Q24371, Q38741, Q3UIW5, Q3UJP5, Q4VBF2, Q58D79, Q5BKU9, Q5EA28, Q5XI59, Q657C0, Q67V61, Q6AVZ9, Q6DRL4, Q6NVV7, Q757Y7, Q75LH6, Q768S4, Q8BQ33, Q8K1S6, Q8R3A2, Q8R4R9, Q8R4S0, Q8RWM3, Q8TAE6

Diamond homologs: O82239, Q5Z8R1, Q8VIG6, Q9BWF2, B1AUE5, E9QAU8, G2Q0E2, O49500, P90990, Q08CN9, Q0II22, Q0V9R0, Q500V2, Q5PP23, Q5QLR5, Q5R476, Q66J97, Q6NPT7, Q6NRV8, Q6ZNA4, Q6ZSG1, Q71FD5, Q7XTV7, Q8GT74, Q8GYT9, Q8NHG8, Q90ZT7, Q99ML9, Q9BV68, Q9C919, Q9FL42, Q9FMM4, Q9LQX2, Q9VHI7, Q9VI20, Q9ZQF9, A5WWA0, F4I2Y3, O22197, O43567

SIGNOR signaling

1 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
Antigen processing: Ubiquitination & Proteasome degradation	8	15.7×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein polyubiquitination	5	22.2×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	3
Uncertain significance	87
Likely benign	93
Benign	17

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2168671	NM_005879.3(TRAIP):c.836del (p.Asn279fs)	Pathogenic
221232	NM_005879.3(TRAIP):c.553C>T (p.Arg185Ter)	Pathogenic
221233	NM_005879.3(TRAIP):c.52C>T (p.Arg18Cys)	Pathogenic
2425431	NC_000003.11:g.(?49877205)(49882013_?)del	Pathogenic
2698999	NM_005879.3(TRAIP):c.878del (p.Val292_Leu293insTer)	Pathogenic
2810768	NM_005879.3(TRAIP):c.66_81dup (p.Thr28fs)	Pathogenic
2989649	NM_005879.3(TRAIP):c.169del (p.Thr57fs)	Pathogenic
2991455	NM_005879.3(TRAIP):c.301C>T (p.Gln101Ter)	Pathogenic
2998164	NM_005879.3(TRAIP):c.349del (p.Thr117fs)	Pathogenic
3646873	NM_005879.3(TRAIP):c.724G>T (p.Glu242Ter)	Pathogenic
3698997	NM_005879.3(TRAIP):c.654_655del (p.Glu220fs)	Pathogenic
4819264	P47L	Pathogenic
2119077	NM_005879.3(TRAIP):c.796-2A>G	Likely pathogenic
3067877	NM_005879.3(TRAIP):c.1093C>T (p.Gln365Ter)	Likely pathogenic
4696593	NM_005879.3(TRAIP):c.98+2T>G	Likely pathogenic

SpliceAI

2964 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49830069:C:CC	acceptor_gain	1.0000
3:49831914:A:AC	donor_gain	1.0000
3:49831915:C:CC	donor_gain	1.0000
3:49839859:CT:C	acceptor_gain	1.0000
3:49839861:C:CC	acceptor_gain	1.0000
3:49839862:T:C	acceptor_gain	1.0000
3:49841824:A:AC	donor_gain	1.0000
3:49841825:C:CC	donor_gain	1.0000
3:49841825:CTT:C	donor_gain	1.0000
3:49842451:A:AC	donor_gain	1.0000
3:49842452:C:CC	donor_gain	1.0000
3:49843799:A:AC	donor_gain	1.0000
3:49843800:C:CC	donor_gain	1.0000
3:49848196:TTAGG:T	acceptor_gain	1.0000
3:49856353:CAC:C	donor_loss	1.0000
3:49856354:A:AC	donor_gain	1.0000
3:49856354:AC:A	donor_gain	1.0000
3:49856355:C:CC	donor_gain	1.0000
3:49856355:CC:C	donor_gain	1.0000
3:49856355:CCA:C	donor_gain	1.0000
3:49856355:CCACT:C	donor_gain	1.0000
3:49830014:TCTTA:T	donor_loss	0.9900
3:49830015:CTTAC:C	donor_loss	0.9900
3:49830016:TTA:T	donor_loss	0.9900
3:49830017:TA:T	donor_loss	0.9900
3:49830018:A:C	donor_loss	0.9900
3:49830064:GGGAG:G	acceptor_gain	0.9900
3:49830065:GGAG:G	acceptor_gain	0.9900
3:49830066:GAG:G	acceptor_gain	0.9900
3:49830067:AGCT:A	acceptor_loss	0.9900

AlphaMissense

3080 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49856367:G:C	F29L	1.000
3:49856367:G:T	F29L	1.000
3:49856369:A:G	F29L	1.000
3:49848153:C:G	C49S	0.999
3:49848154:A:G	C49R	0.999
3:49848154:A:T	C49S	0.999
3:49848159:G:T	P47Q	0.999
3:49848163:A:G	C46R	0.999
3:49848188:C:A	W37C	0.999
3:49848188:C:G	W37C	0.999
3:49848190:A:G	W37R	0.999
3:49848190:A:T	W37R	0.999
3:49856357:A:G	C33R	0.999
3:49856368:A:G	F29S	0.999
3:49856373:G:C	H27Q	0.999
3:49856373:G:T	H27Q	0.999
3:49856375:G:C	H27D	0.999
3:49856377:C:A	G26V	0.999
3:49856377:C:T	G26D	0.999
3:49856381:A:G	C25R	0.999
3:49856389:G:T	A22D	0.999
3:49856426:A:G	C10R	0.999
3:49856433:G:C	C7W	0.999
3:49856434:C:G	C7S	0.999
3:49856434:C:T	C7Y	0.999
3:49856435:A:G	C7R	0.999
3:49856435:A:T	C7S	0.999
3:49847576:G:C	F63L	0.998
3:49847576:G:T	F63L	0.998
3:49847578:A:G	F63L	0.998

dbSNP variants (sampled 300 via entrez): RS1000097407 (3:49857137 C>G), RS1000275696 (3:49845567 C>T), RS1000323612 (3:49830499 C>A,T), RS1000339542 (3:49842003 C>T), RS1000356671 (3:49838422 T>A,G), RS1000387924 (3:49837873 C>G,T), RS1000484699 (3:49834399 C>T), RS1000496574 (3:49844344 G>A), RS1000689740 (3:49836571 C>A,T), RS1001002977 (3:49851622 C>G,T), RS1001093669 (3:49857716 A>G), RS1001358078 (3:49839917 T>C), RS1001418423 (3:49839330 T>C), RS1001529655 (3:49856619 C>G), RS1001678334 (3:49848715 T>C)

Disease associations

OMIM: gene MIM:605958 | disease phenotypes: MIM:616777

GenCC curated gene-disease

Disease	Classification	Inheritance
Seckel syndrome 9	Strong	Autosomal recessive
Seckel syndrome	Supportive	Autosomal recessive

Mondo (2): Seckel syndrome 9 (MONDO:0014767), Seckel syndrome (MONDO:0019342)

Orphanet (1): Seckel syndrome (Orphanet:808)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000062	Ambiguous genitalia
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000387	Absent earlobe
HP:0000411	Protruding ear
HP:0000444	Convex nasal ridge
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000682	Abnormal dental enamel morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000998	Hypertrichosis
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001762	Talipes equinovarus
HP:0001852	Sandal gap

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST005316_109	Intelligence (MTAG)	2.000000e-11
GCST006920_7	Regular attendance at a gym or sports club	6.000000e-10
GCST006922_9	Regular attendance at a religious group	3.000000e-08
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007614_40	C-reactive protein levels	6.000000e-10
GCST008529_17	Tea consumption	9.000000e-08
GCST008549_12	Mental health study participation (provided email address)	2.000000e-08
GCST009524_1	Household income (MTAG)	4.000000e-10
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST011122_42	Walking pace	3.000000e-10
GCST012332_54	Multisite chronic pain	4.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009592	social interaction measurement
EFO:0004458	C-reactive protein measurement
EFO:0010091	tea consumption measurement
EFO:0010130	health study participation
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0010100	multisite chronic pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, decreases expression, decreases methylation	4
Acetaminophen	increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
zinc chromate	decreases expression, increases abundance	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	affects expression	1
Gallic Acid	decreases expression	1
Menthol	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Rotenone	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03139903	Not specified	COMPLETED	The Primordial Dwarfisms: Diagnosis, Identification of the Molecular Basis of Seckel Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Type II