AFF3

Summary

AFF3 (ALF transcription elongation factor 3, HGNC:6473) is a protein-coding gene on chromosome 2q11.2, encoding AF4/FMR2 family member 3 (P51826). Putative transcription activator that may function in lymphoid development and oncogenesis.

This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene.

Source: NCBI Gene 3899 — RefSeq curated summary.

At a glance

• Gene–disease (curated): KINSSHIP syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 91
• Clinical variants (ClinVar): 327 total — 8 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 63
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_001386135

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6473
Approved symbol	AFF3
Name	ALF transcription elongation factor 3
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	MLLT2-like
Ensembl gene	ENSG00000144218
Ensembl biotype	protein_coding
OMIM	601464
Entrez	3899

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 18 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000317233, ENST00000409236, ENST00000409579, ENST00000415384, ENST00000416492, ENST00000423966, ENST00000424600, ENST00000427118, ENST00000430789, ENST00000432037, ENST00000440445, ENST00000441400, ENST00000445815, ENST00000483600, ENST00000498090, ENST00000671937, ENST00000672047, ENST00000672197, ENST00000672204, ENST00000672269, ENST00000672756, ENST00000672822, ENST00000672857, ENST00000672999, ENST00000673232, ENST00000673328, ENST00000673529, ENST00000683540

RefSeq mRNA: 3 — MANE Select: NM_001386135 NM_001025108, NM_001386135, NM_002285

CCDS: CCDS33258, CCDS42723

Canonical transcript exons

ENST00000672756 — 25 exons

Exon	Start	End
ENSE00000964064	100007148	100007460
ENSE00000964068	99752221	99752301
ENSE00001038861	99672538	99672589
ENSE00001038862	99582798	99582999
ENSE00001038863	99837477	99837524
ENSE00001038866	99727077	99727128
ENSE00001038869	99554683	99554732
ENSE00001038871	99560365	99560436
ENSE00001038873	99568852	99568915
ENSE00001038876	99593195	99594289
ENSE00001038878	99565487	99565623
ENSE00001038880	99744104	99744140
ENSE00001038882	99601435	99601621
ENSE00001038884	99554311	99554534
ENSE00001038888	99558875	99558968
ENSE00001038890	99578327	99578451
ENSE00001038893	99649626	99649666
ENSE00001072237	100006632	100007017
ENSE00001217678	100008812	100008932
ENSE00001587550	99545419	99551595
ENSE00001618869	100129224	100129306
ENSE00002485467	99587154	99587278
ENSE00003586748	100105504	100105583
ENSE00003790625	100104402	100104518
ENSE00003891481	100142484	100142590

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 98.80.

FANTOM5 (CAGE): breadth broad, TPM avg 8.9335 / max 890.7591, expressed in 587 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29905	3.7839	143
29906	2.5220	155
29904	0.8408	87
29901	0.4828	188
29899	0.3440	134
29902	0.3380	163
29907	0.2572	74
29908	0.1858	64
29900	0.1549	63
29903	0.0180	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.80	gold quality
ganglionic eminence	UBERON:0004023	92.29	gold quality
postcentral gyrus	UBERON:0002581	91.45	gold quality
lower lobe of lung	UBERON:0008949	90.69	gold quality
parietal lobe	UBERON:0001872	90.54	gold quality
mammary duct	UBERON:0001765	89.25	gold quality
pons	UBERON:0000988	89.12	gold quality
calcaneal tendon	UBERON:0003701	88.83	gold quality
superior frontal gyrus	UBERON:0002661	88.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.57	gold quality
cerebellar vermis	UBERON:0004720	87.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.98	gold quality
entorhinal cortex	UBERON:0002728	86.90	gold quality
sural nerve	UBERON:0015488	86.05	gold quality
cerebellar cortex	UBERON:0002129	85.94	gold quality
cerebellar hemisphere	UBERON:0002245	85.79	gold quality
cerebellum	UBERON:0002037	85.78	gold quality
superficial temporal artery	UBERON:0001614	85.72	gold quality
epithelium of mammary gland	UBERON:0003244	85.36	gold quality
lymph node	UBERON:0000029	85.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.98	gold quality
prostate gland	UBERON:0002367	84.85	gold quality
substantia nigra pars compacta	UBERON:0001965	84.62	gold quality
tendon	UBERON:0000043	84.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.83	gold quality
superior vestibular nucleus	UBERON:0007227	83.71	gold quality
mammary gland	UBERON:0001911	83.64	gold quality
thoracic mammary gland	UBERON:0005200	83.60	gold quality
spleen	UBERON:0002106	83.22	gold quality
trabecular bone tissue	UBERON:0002483	83.21	gold quality

Single-cell (SCXA)

Detected in 24 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4538.72
E-MTAB-10042	yes	978.98
E-GEOD-130473	yes	701.68
E-HCAD-4	yes	128.86
E-CURD-7	yes	116.39
E-ENAD-21	yes	116.39
E-CURD-122	yes	87.37
E-HCAD-35	yes	63.85
E-CURD-88	yes	52.50
E-CURD-112	yes	45.09
E-MTAB-9221	yes	23.18
E-MTAB-9467	yes	21.49
E-ANND-3	yes	21.32
E-HCAD-10	yes	18.83
E-MTAB-9067	yes	18.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

210 targeting AFF3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955

Literature-anchored findings (GeneRIF, showing 19)

• The LAF4 gene mapped on chromosome region 2q11.2-q12 has been identified as a fusion partner of the MLL gene in a case of infant acute lymphoblastic leukemia. (PMID:12203795)
• This gene is fused to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23). (PMID:12743608)
• LAF-4 may be a proto-oncogene that is transcriptionally activated in some cases of breast cancer. (PMID:15704140)
• array comparative genomic hybridization (CGH) analysis revealed a de novo interstitial microdeletion of 500 kb on chromosome 2q11.1 containing the LAF4/AFF3 (lymphoid-nuclear-protein-related AF4) gene (PMID:18616733)
• A novel fusion 5’AFF3/3’BCL2 originated from a t(2;18)(q11.2;q21.33) translocation in follicular lymphoma. (PMID:18622426)
• AFF3 is a novel rheumatoid arthritis susceptibile gene. (PMID:19359276)
• overexpression of AFF2/3/4 interferes with the organization and/or biogenesis of nuclear speckles. (PMID:21330300)
• Significant evidence for association of AFF3 rs10865035 with systgemic lupus erythmatgosus was detected. (PMID:22983539)
• FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat. (PMID:24763282)
• Both the AFF3 and NTM triglyceride associations were replicated among Multi-ethnic Study of Atherosclerosis study participants (P = 1.00 x 10(-7) and 8.00 x 10(-5), respectively). (PMID:25819087)
• Data identified AFF3 as an interactive protein with beclin1 and suggest that AFF3 is probably a key regulator of Beclin-1. (PMID:28401970)
• AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference-mediated gene knockdown reversed this phenotype. (PMID:30326937)
• Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. (PMID:33961779)
• Association of AFF3 Gene Polymorphism rs10865035 with Rheumatoid Arthritis: A Population-Based Case-Control Study on a Pakistani Cohort. (PMID:34104118)
• A novel variant in AFF3 underlying isolated syndactyly. (PMID:36273379)
• Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants. (PMID:36576140)
• Loss of AR-regulated AFF3 contributes to prostate cancer progression and reduces ferroptosis sensitivity by downregulating ACSL4 based on single-cell sequencing analysis. (PMID:38478171)
• Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles. (PMID:38811945)
• Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms. (PMID:38886730)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aff3	ENSMUSG00000037138
rattus_norvegicus	Aff3	ENSRNOG00000018830
drosophila_melanogaster	lilli	FBGN0041111

Paralogs (3): AFF4 (ENSG00000072364), AFF2 (ENSG00000155966), AFF1 (ENSG00000172493)

Protein

Protein identifiers

AF4/FMR2 family member 3 — P51826 (reviewed: P51826)

Alternative names: Lymphoid nuclear protein related to AF4

All UniProt accessions (17): P51826, A0A5F9ZHE5, A0A5F9ZHH7, A0A5F9ZHU9, A0A5F9ZHV2, A0A5F9ZHV9, A0A5F9ZHZ1, C9J622, C9J847, C9JC67, C9JIB1, C9JMS1, C9JUC4, C9JUY1, C9JZ66, H7C3W3, H7C4C2

UniProt curated annotations — full annotation on UniProt →

Function. Putative transcription activator that may function in lymphoid development and oncogenesis. Binds, in vitro, to double-stranded DNA.

Subcellular location. Nucleus.

Tissue specificity. Preferentially expressed in lymphoid tissues, highest levels being found in the thymus.

Disease relevance. KINSSHIP syndrome (KINS) [MIM:619297] An autosomal dominant disease characterized by developmental delay, impaired intellectual development, seizures, short stature, mesomelic dysplasia, dysmorphic facial features, horseshoe or hypoplastic kidney, and failure to thrive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AF4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P51826-1	1	yes
P51826-2	2

RefSeq proteins (3): NP_001020279, NP_001373064, NP_002276 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007797	AF4/FMR2	Family
IPR043639	AF4_int	Conserved_site
IPR043640	AF4/FMR2_CHD	Domain

Pfam: PF05110, PF18875, PF18876

UniProt features (44 total): compositionally biased region 18, sequence variant 9, region of interest 8, sequence conflict 5, modified residue 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51826-F1	52.20	0.15

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 (2): 755, 881

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 452 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, HNF3ALPHA_Q6, GOBP_RESPONSE_TO_PEPTIDE, GOBP_HINDLIMB_MORPHOGENESIS, GOZGIT_ESR1_TARGETS_DN, AREB6_01, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, TAL1ALPHAE47_01, DARWICHE_PAPILLOMA_PROGRESSION_RISK, CACCAGC_MIR138, CHX10_01, GTACAGG_MIR486

GO Biological Process (4): regulation of gene expression (GO:0010468), response to tumor necrosis factor (GO:0034612), embryonic hindlimb morphogenesis (GO:0035116), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (3): double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), DNA binding (GO:0003677)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), nuclear body (GO:0016604), super elongation complex (GO:0032783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
gene expression	1
regulation of macromolecule biosynthetic process	1
response to cytokine	1
embryonic limb morphogenesis	1
hindlimb morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
DNA binding	1
transcription cis-regulatory region binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
nucleic acid binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
transcription elongation factor complex	1

Protein interactions and networks

STRING

1590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFF3	MLLT3	P42568	841
AFF3	EAF1	Q96JC9	793
AFF3	MLLT1	Q03111	770
AFF3	AFF4	Q9UHB7	656
AFF3	ELL	P55199	653
AFF3	LONRF2	Q1L5Z9	651
AFF3	PTPN22	Q9Y2R2	622
AFF3	MLLT10	P55197	615
AFF3	KIF5A	Q12840	583
AFF3	KMT2A	Q03164	582
AFF3	MLLT6	P55198	574
AFF3	AFF2	P51816	561
AFF3	SUB1	P53999	556
AFF3	ELL2	O00472	542
AFF3	CCNT1	O60563	521

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
MLLT1	ELL2	psi-mi:“MI:0914”(association)	0.640
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
AFF3	ERP29	psi-mi:“MI:0915”(physical association)	0.400
AFF3	TFRC	psi-mi:“MI:0915”(physical association)	0.400
SYT2	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
DISC1	AFF3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-RNA), AFF3 (Affinity Capture-RNA), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Proximity Label-MS), AFF3 (Proximity Label-MS), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Affinity Capture-MS), AFF3 (Negative Genetic), AFF3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, E9Q9M8, F7AQ22, G3V8T1, O75152, O75376, P49140, P51826, P97432, Q13625, Q14596, Q17R98, Q1LY51, Q3TYA6, Q4KKX4, Q4LE39, Q4R6F6, Q501R9, Q505G8, Q5F3Z9, Q5HYC2, Q5RC94, Q5XJV7, Q60974, Q68FE8, Q69Z61, Q6A098, Q6NXK2, Q6NZF1, Q6PJT7, Q6ZNC4, Q86YI8, Q8BFU3, Q8BJ05, Q8CCH7, Q8CG79, Q8CHY6, Q8K2W6, Q8ND24

Diamond homologs: B3MLB7, B3NAM7, B4JQ42, B4KFE1, B4LV24, B4MUE1, B4NXA8, O55112, P51816, P51826, P51827, Q29KG4, Q7YQM1, Q7YQM2, Q9ESC8, Q9UHB7, Q9VQI9, P51825, O88573

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CTNNB1	“up-regulates quantity by expression”	AFF3	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — LUAD, WDTC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	219
Likely benign	52
Benign	15

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1077075	NM_001386135.1(AFF3):c.697G>T (p.Ala233Ser)	Pathogenic
1077077	NM_001386135.1(AFF3):c.691C>T (p.Pro231Ser)	Pathogenic
1077078	NM_001386135.1(AFF3):c.692C>T (p.Pro231Leu)	Pathogenic
1077079	NM_001386135.1(AFF3):c.704T>G (p.Val235Gly)	Pathogenic
1338773	NM_001386135.1(AFF3):c.692_693delinsGA (p.Pro231Arg)	Pathogenic
430951	NM_001386135.1(AFF3):c.697G>A (p.Ala233Thr)	Pathogenic
59147	GRCh38/hg38 2q11.2-13(chr2:97672522-110211318)x3	Pathogenic
60183	GRCh38/hg38 2q11.2(chr2:98787057-100785053)x1	Pathogenic
1331568	NM_001386135.1(AFF3):c.713T>C (p.Met238Thr)	Likely pathogenic
150339	GRCh38/hg38 2q11.2(chr2:98411773-101636907)x1	Likely pathogenic
2444285	NM_001386135.1(AFF3):c.1548del (p.Ser517fs)	Likely pathogenic
3383399	NM_001386135.1(AFF3):c.417del (p.Gln139fs)	Likely pathogenic
976685	NM_001386135.1(AFF3):c.713T>G (p.Met238Arg)	Likely pathogenic

SpliceAI

7105 predictions. Top by Δscore:

Variant	Effect	Δscore
2:100104398:TTA:T	donor_loss	1.0000
2:100104399:TA:T	donor_loss	1.0000
2:100104401:C:CA	donor_loss	1.0000
2:100104401:CCA:C	donor_gain	1.0000
2:99551591:GAATT:G	acceptor_gain	1.0000
2:99551593:ATT:A	acceptor_gain	1.0000
2:99551594:TT:T	acceptor_gain	1.0000
2:99551594:TTC:T	acceptor_loss	1.0000
2:99551595:TCTA:T	acceptor_loss	1.0000
2:99551596:C:CC	acceptor_gain	1.0000
2:99551596:C:CG	acceptor_loss	1.0000
2:99551597:T:G	acceptor_loss	1.0000
2:99554306:CTCA:C	donor_loss	1.0000
2:99554307:TCACC:T	donor_loss	1.0000
2:99554308:CA:C	donor_loss	1.0000
2:99554309:A:AC	donor_gain	1.0000
2:99554310:C:CC	donor_gain	1.0000
2:99554310:C:CG	donor_loss	1.0000
2:99554310:CCT:C	donor_gain	1.0000
2:99554681:A:AC	donor_gain	1.0000
2:99554682:C:CC	donor_gain	1.0000
2:99568913:GGC:G	acceptor_gain	1.0000
2:99568916:C:CC	acceptor_gain	1.0000
2:99568916:CTACA:C	acceptor_loss	1.0000
2:99568917:T:G	acceptor_loss	1.0000
2:99578325:A:AC	donor_gain	1.0000
2:99578326:C:CC	donor_gain	1.0000
2:99582998:CA:C	acceptor_gain	1.0000
2:99583000:C:CC	acceptor_gain	1.0000
2:99587149:CGTA:C	donor_loss	1.0000

AlphaMissense

8101 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:100006797:C:A	R236S	1.000
2:100006797:C:G	R236S	1.000
2:100006798:C:A	R236M	1.000
2:100006798:C:G	R236T	1.000
2:99551508:A:G	L1216P	1.000
2:99551511:C:T	G1215D	1.000
2:99551512:C:G	G1215R	1.000
2:99551532:A:G	L1208P	1.000
2:99551580:A:G	L1192P	1.000
2:99554337:G:T	A1178D	1.000
2:99554338:C:G	A1178P	1.000
2:99554345:C:A	W1175C	1.000
2:99554345:C:G	W1175C	1.000
2:99554347:A:G	W1175R	1.000
2:99554347:A:T	W1175R	1.000
2:99554357:G:C	S1171R	1.000
2:99554357:G:T	S1171R	1.000
2:99554359:T:G	S1171R	1.000
2:99554364:A:G	L1169P	1.000
2:99554385:A:T	V1162D	1.000
2:99554388:T:G	H1161P	1.000
2:99554389:G:C	H1161D	1.000
2:99554395:C:G	A1159P	1.000
2:99554397:G:T	A1158E	1.000
2:99554398:C:G	A1158P	1.000
2:99554409:A:C	I1154S	1.000
2:99554409:A:G	I1154T	1.000
2:99554409:A:T	I1154N	1.000
2:99558879:A:G	F1094S	1.000
2:99558891:A:C	L1090R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000111 (2:99920346 G>A), RS1000004773 (2:99674835 C>T), RS1000008035 (2:99810967 G>A), RS1000009116 (2:99610974 C>A,T), RS1000012599 (2:99570805 G>A), RS1000019064 (2:99874171 C>T), RS1000035602 (2:99639541 C>G), RS1000051193 (2:99794507 T>C,G), RS1000053393 (2:100044131 C>A,T), RS1000077592 (2:100127491 T>C), RS1000078404 (2:99797889 C>A,T), RS1000079202 (2:100084731 A>G,T), RS1000080069 (2:100060750 G>A), RS1000092121 (2:99878591 C>T), RS1000092438 (2:99836902 G>A)

Disease associations

OMIM: gene MIM:601464 | disease phenotypes: MIM:619297

GenCC curated gene-disease

Disease	Classification	Inheritance
KINSSHIP syndrome	Strong	Autosomal dominant
intellectual disability	Moderate	Autosomal dominant

Mondo (2): KINSSHIP syndrome (MONDO:0851095), intellectual disability (MONDO:0001071)

Orphanet (0):

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000085	Horseshoe kidney
HP:0000089	Renal hypoplasia
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000637	Long palpebral fissure
HP:0000639	Nystagmus
HP:0000664	Synophrys
HP:0000687	Widely spaced teeth
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000891	Cervical ribs
HP:0000938	Osteopenia
HP:0000954	Single transverse palmar crease
HP:0000960	Sacral dimple
HP:0000998	Hypertrichosis
HP:0001249	Intellectual disability
HP:0001252	Hypotonia

GWAS associations

91 associations (top):

Study	Trait	p-value
GCST000038_10	Type 1 diabetes	5.000000e-06
GCST001688_3	Type 1 diabetes nephropathy	1.000000e-08
GCST001688_5	Type 1 diabetes nephropathy	3.000000e-07
GCST002318_130	Rheumatoid arthritis	2.000000e-18
GCST002318_4	Rheumatoid arthritis	1.000000e-14
GCST002434_2	Rheumatoid arthritis	2.000000e-08
GCST003465_10	Cannabis dependence symptom count	2.000000e-06
GCST003795_2	Age at first birth	3.000000e-09
GCST003862_2	Kidney disease (end stage renal disease vs non-end stage renal disease) in type 1 diabetes	4.000000e-07
GCST004364_14	Intelligence	8.000000e-07
GCST004601_27	Red blood cell count	2.000000e-12
GCST004607_218	Plateletcrit	6.000000e-10
GCST005141_76	Cognitive ability (MTAG)	2.000000e-11
GCST005142_24	Cognitive ability	6.000000e-07
GCST005316_177	Intelligence (MTAG)	6.000000e-17
GCST005316_178	Intelligence (MTAG)	5.000000e-17
GCST005316_179	Intelligence (MTAG)	3.000000e-09
GCST005316_180	Intelligence (MTAG)	3.000000e-09
GCST005316_181	Intelligence (MTAG)	1.000000e-14
GCST005316_182	Intelligence (MTAG)	4.000000e-10
GCST005316_184	Intelligence (MTAG)	3.000000e-10
GCST005316_187	Intelligence (MTAG)	3.000000e-10
GCST005316_287	Intelligence (MTAG)	9.000000e-12
GCST005316_289	Intelligence (MTAG)	4.000000e-10
GCST005316_341	Intelligence (MTAG)	1.000000e-12
GCST005316_343	Intelligence (MTAG)	9.000000e-10
GCST005316_345	Intelligence (MTAG)	2.000000e-14
GCST005528_3	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	8.000000e-07
GCST005536_30	Type 1 diabetes	1.000000e-07
GCST005568_29	Rheumatoid arthritis (ACPA-positive)	2.000000e-11

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0008457	cannabis dependence measurement
EFO:0009101	age at first birth measurement
EFO:0004337	intelligence
EFO:0004305	erythrocyte count
EFO:0007985	platelet crit
EFO:0004784	self reported educational attainment
EFO:0004695	intraocular pressure measurement
EFO:0006941	grip strength measurement
EFO:0005128	albumin:globulin ratio measurement
EFO:0009102	number of children ever born measurement
EFO:0009592	social interaction measurement
EFO:0009695	household income
EFO:0010343	cholesteryl ester 18:0 measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0010100	multisite chronic pain
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0010701	mean reticulocyte volume
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
bisphenol A	increases methylation, increases expression, affects cotreatment	3
sodium arsenite	affects methylation, increases expression	3
Calcitriol	decreases expression, increases expression, affects cotreatment	3
Aflatoxin B1	decreases methylation, increases methylation	3
Tretinoin	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
senecionine	decreases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
trichostatin A	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
enzalutamide	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Decitabine	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

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

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