FREM1

Summary

FREM1 (FRAS1 related extracellular matrix 1, HGNC:23399) is a protein-coding gene on chromosome 9p22.3, encoding FRAS1-related extracellular matrix protein 1 (Q5H8C1). Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.

The products of this gene play important roles both in embryonic development and as a modulator of the innate immune responses and inflammation. This gene encodes an extracellular matrix protein that is restricted to the dermis. It is secreted and forms complexes with FREM2 and FRAS1 gene products and is required to maintain epidermal adhesion during embryonic development. Pathogenic mutations in this gene have been implicated in Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and congenital diaphragmatic hernia (CDH). A 715 aa isoform of this gene known as TILRR (Toll-like interleukin-receptor regulator) is expressed from an alternate promoter and is involved in controlling the inflammatory process. The encoded protein is a cell surface proteoglycan that is a co-receptor for IL-1 receptor type I (IL1RI). TILRR increases IL1R1 expression levels and regulates receptor function, leading to amplified activation of NF-kappaB and inflammatory responses.

Source: NCBI Gene 158326 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculotrichoanal syndrome (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,495 total — 26 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_001379081

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23399
Approved symbol	FREM1
Name	FRAS1 related extracellular matrix 1
Location	9p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25461, C9orf145, C9orf143, DKFZp686M16108, TILRR
Ensembl gene	ENSG00000164946
Ensembl biotype	protein_coding
OMIM	608944
Entrez	158326

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000380875, ENST00000380880, ENST00000380894, ENST00000427623, ENST00000466679, ENST00000485068, ENST00000486223, ENST00000497634, ENST00000895028

RefSeq mRNA: 5 — MANE Select: NM_001379081 NM_001177704, NM_001370058, NM_001370061, NM_001379081, NM_144966

CCDS: CCDS47952, CCDS55293

Canonical transcript exons

ENST00000380880 — 37 exons

Exon	Start	End
ENSE00001486604	14868744	14869244
ENSE00001486606	14909914	14910428
ENSE00001486630	14775789	14776203
ENSE00001486644	14801652	14801874
ENSE00001486646	14804956	14805152
ENSE00001486648	14806661	14806846
ENSE00001486650	14807940	14808134
ENSE00001486652	14812812	14813064
ENSE00001486653	14816778	14816871
ENSE00001486656	14819234	14819442
ENSE00001486657	14823160	14823327
ENSE00001486658	14824025	14824115
ENSE00001486660	14824796	14824992
ENSE00001486661	14841447	14841589
ENSE00001486663	14842316	14842660
ENSE00001486664	14845960	14846091
ENSE00001486667	14848665	14848773
ENSE00001486670	14851284	14851607
ENSE00001486674	14857553	14857749
ENSE00001486678	14859183	14859484
ENSE00001486680	14863809	14863903
ENSE00001486704	14737152	14737595
ENSE00003255841	14797498	14797642
ENSE00003469116	14770605	14770806
ENSE00003478303	14747264	14747428
ENSE00003493423	14750127	14750276
ENSE00003507152	14784370	14784634
ENSE00003526063	14740149	14740234
ENSE00003528380	14756374	14756446
ENSE00003569849	14746923	14747051
ENSE00003570089	14769724	14769868
ENSE00003582010	14792743	14792884
ENSE00003597015	14759772	14759901
ENSE00003609845	14748401	14748639
ENSE00003628891	14788919	14789114
ENSE00003687017	14747681	14747728
ENSE00003693684	14746353	14746468

Expression profiles

Bgee: expression breadth ubiquitous, 171 present calls, max score 88.52.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2694 / max 135.3883, expressed in 360 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100042	0.3626	143
100050	0.3262	137
100044	0.2800	112
100045	0.2716	116
100046	0.2515	111
100047	0.1297	68
100043	0.1182	73
100051	0.0865	52
100052	0.0840	44
100048	0.0784	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	88.52	silver quality
smooth muscle tissue	UBERON:0001135	87.53	gold quality
metanephros	UBERON:0000081	86.74	gold quality
body of uterus	UBERON:0009853	86.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.75	gold quality
cerebellar hemisphere	UBERON:0002245	85.27	gold quality
metanephros cortex	UBERON:0010533	85.19	gold quality
cerebellar cortex	UBERON:0002129	85.12	gold quality
adrenal tissue	UBERON:0018303	85.10	gold quality
descending thoracic aorta	UBERON:0002345	84.56	gold quality
thoracic aorta	UBERON:0001515	84.31	gold quality
body of pancreas	UBERON:0001150	84.30	gold quality
ascending aorta	UBERON:0001496	84.30	gold quality
aorta	UBERON:0000947	83.77	gold quality
cerebellum	UBERON:0002037	83.54	gold quality
popliteal artery	UBERON:0002250	83.53	gold quality
tibial artery	UBERON:0007610	83.50	gold quality
right coronary artery	UBERON:0001625	83.43	gold quality
corpus epididymis	UBERON:0004359	82.94	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.09	gold quality
adult mammalian kidney	UBERON:0000082	81.96	gold quality
kidney	UBERON:0002113	80.69	gold quality
colonic epithelium	UBERON:0000397	80.59	gold quality
left coronary artery	UBERON:0001626	80.41	gold quality
small intestine	UBERON:0002108	80.25	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.05	gold quality
coronary artery	UBERON:0001621	79.70	gold quality
cortex of kidney	UBERON:0001225	79.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.19	gold quality
left uterine tube	UBERON:0001303	78.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	46.31
E-ANND-3	yes	6.95
E-MTAB-9801	yes	6.57
E-GEOD-76312	no	215.59

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NPNT	Activation

miRNA regulators (miRDB)

105 targeting FREM1, 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-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4753-3P	99.90	71.03	3786

Literature-anchored findings (GeneRIF, showing 21)

• The phenotypic variability reported for different Frem1 mouse mutants suggests that the apparently distinct phenotype of bifid nose and anorectal and renal anomalies syndrome in humans may represent a previously unrecognized variant of Fraser syndrome. (PMID:19732862)
• TILRR, an isoform encoded by an alternatively spliced FREM1 mRNA, is an IL-1RI co-receptor that associates with the signaling receptor complex to enhance recruitment of MyD88 and control Ras-dependent amplification of NF-kappaB and inflammatory responses. (PMID:19940113)
• Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. FREM1 deficiency ties the molecular cause of MOTA syndrome closely to the pathogenesis of Fraser syndrome. (PMID:21507892)
• These data suggest that copy number variations and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. (PMID:21931569)
• a role for TILRR in selective amplification of NF-kappaB responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment. (PMID:22262840)
• The location of the IBD region 16 kb from FREM1 suggests the phenotype in Manitoba oculotrichoanal syndrome patients is attributable to a variant outside of FREM1, potentially in a regulatory element. (PMID:22690109)
• FREM1 encodes a basement membrane protein of FRAS1-related extracellular matrix protein 1 which is required for epidermal adhesion during embryonic development (PMID:22876578)
• The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection. (PMID:22915813)
• We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice. (PMID:23221805)
• Disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes. (PMID:23401257)
• In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. (PMID:24700879)
• FREM1 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• this report describes a patient with a phenotype compatible with Manitoba-oculo-tricho-anal syndrome in whom two novel FREM1 mutations were identified in the compound heterozygous state thus broadening the mutational spectrum of the disease. (PMID:28111185)
• we identified genome-wide significant association involving measures of central upper lip height at 9p22 within FREM1 (PMID:28441456)
• Our results showed that p.Arg2167Trp had a weaker effect in interrupting interactions between FREM2 and FREM1 than FS-associated missense mutation p.Glu1972Lys. Overall, our data demonstrate that the homozygous mutation p.Arg2167Trp in FREM2 causes isolated Cryptophthalmos(CO), which will facilitate our better understanding of the molecular mechanisms underlying the disease (PMID:29688405)
• Toll-like Interleukin 1 Receptor Regulator Is an Important Modulator of Inflammation Responsive Genes. (PMID:30873160)
• Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (PMID:32926405)
• Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. (PMID:33038106)
• Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high-level immune infiltration status. (PMID:33058542)
• High level of plasma TILRR protein is associated with faster HIV seroconversion. (PMID:35339895)
• Two novel mutations within FREM1 gene in patients with bifid nose. (PMID:38097983)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	frem1a	ENSDARG00000069473
mus_musculus	Frem1	ENSMUSG00000059049
rattus_norvegicus	Frem1	ENSRNOG00000022309

Paralogs (7): SLC8A3 (ENSG00000100678), SLC8A2 (ENSG00000118160), FRAS1 (ENSG00000138759), FREM2 (ENSG00000150893), ADGRV1 (ENSG00000164199), SLC8A1 (ENSG00000183023), FREM3 (ENSG00000183090)

Protein

Protein identifiers

FRAS1-related extracellular matrix protein 1 — Q5H8C1 (reviewed: Q5H8C1)

Alternative names: Protein QBRICK

All UniProt accessions (2): F8WE85, Q5H8C1

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.

Subunit / interactions. Interacts with FREM2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane.

Disease relevance. Bifid nose, with or without anorectal and renal anomalies (BNAR) [MIM:608980] A disease characterized by the presence of a bifid nose usually associated with renal agenesis and anorectal malformations. A bifid nose is a congenital deformity due to failure of the paired nasal processes to fuse to a single midline organ during early gestation. The disease is caused by variants affecting the gene represented in this entry. Manitoba oculotrichoanal syndrome (MOTA) [MIM:248450] A rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. The disease is caused by variants affecting the gene represented in this entry. Trigonocephaly 2 (TRIGNO2) [MIM:614485] A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Calx-beta domain binds calcium with high affinity and undergo a major conformational shift upon binding.

Miscellaneous. Was termed QBRICK because it contains 12 repeats: ‘Q’ stands for queen and is taken from the queen being the 12th in a suit of playing card, and ‘BRICK’ stands for the repeating unit.

Similarity. Belongs to the FRAS1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5H8C1-1	1	yes
Q5H8C1-2	2
Q5H8C1-3	3
Q5H8C1-4	4

RefSeq proteins (5): NP_001171175, NP_001356987, NP_001356990, NP_001366010, NP_659403 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR003644	Calx_beta	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR038081	CalX-like_sf	Homologous_superfamily
IPR039005	CSPG_rpt	Repeat
IPR045658	FRAS1-rel_N	Domain
IPR051561	FRAS1_ECM	Family

Pfam: PF00059, PF03160, PF16184, PF19309

UniProt features (50 total): sequence variant 17, repeat 12, splice variant 7, glycosylation site 5, domain 2, short sequence motif 2, sequence conflict 2, signal peptide 1, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5H8C1-F1	75.75	0.07

Functional residue map

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

Disulfide bonds (1): 2151–2165

Glycosylation sites (5): 335, 560, 622, 1014, 1566

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 212 (showing top): GOBP_SKELETAL_SYSTEM_DEVELOPMENT, CAGCTG_AP4_Q5, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT, CCTGTGA_MIR513, AAAGGGA_MIR204_MIR211, GOBP_CRANIAL_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_BONE_MORPHOGENESIS, GOCC_BASEMENT_MEMBRANE, GOBP_EPITHELIAL_STRUCTURE_MAINTENANCE, GOBP_CRANIOFACIAL_SUTURE_MORPHOGENESIS, GOBP_CELL_SUBSTRATE_ADHESION, GOBP_CELL_MATRIX_ADHESION, RIGGI_EWING_SARCOMA_PROGENITOR_UP

GO Biological Process (5): cell communication (GO:0007154), cell-matrix adhesion (GO:0007160), anatomical structure morphogenesis (GO:0009653), craniofacial suture morphogenesis (GO:0097094), cell adhesion (GO:0007155)

GO Molecular Function (3): carbohydrate binding (GO:0030246), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (3): basement membrane (GO:0005604), membrane (GO:0016020), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
binding	2
cellular anatomical structure	2
cell-substrate adhesion	1
developmental process	1
anatomical structure development	1
anatomical structure morphogenesis	1
bone morphogenesis	1
cranial skeletal system development	1
cation binding	1
extracellular matrix	1

Protein interactions and networks

STRING

1534 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FREM1	FRAS1	Q86XX4	931
FREM1	FREM2	Q5SZK8	917
FREM1	GRIP1	Q9Y3R0	846
FREM1	TCF12	Q99081	651
FREM1	VWA2	Q5GFL6	594
FREM1	NPNT	Q6UXI9	564
FREM1	PDGFC	Q9NRA1	473
FREM1	BPIFB2	Q8N4F0	453
FREM1	CCDC171	Q6TFL3	448
FREM1	SCARA3	Q6AZY7	445
FREM1	PGAP4	Q9BRR3	443
FREM1	KIF16B	Q96L93	436
FREM1	GLI2	P10070	428
FREM1	EPHB1	P54762	426
FREM1	MAPK8IP3	Q9UPT6	426

IntAct

4 interactions, top by confidence:

A	B	Type	Score
FREM2	FREM1	psi-mi:“MI:0915”(physical association)	0.400
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): FREM1 (Synthetic Lethality), FREM1 (Affinity Capture-MS), FREM1 (Affinity Capture-MS)

ESM2 similar proteins: B0KW95, B2KI42, B4USZ0, O00222, O18926, O55075, O60245, O94779, P10288, P15116, P19022, P19534, P24503, P33145, P33150, P35400, P39038, P47743, P55283, P55290, P58365, P68500, P70579, P97527, Q07409, Q0E9H9, Q0ZM14, Q14831, Q3B7N0, Q5H8C1, Q5R5W6, Q5R9X1, Q5RDQ8, Q62682, Q62845, Q63149, Q68ED2, Q69Z26, Q8IWV2, Q90275

Diamond homologs: P0C091, Q5H8B9, Q5H8C1, Q5SZK8, Q684R7, Q6NVD0, Q86XX4, Q9GV77, Q9VDG5, Q95J96, Q95LC6, Q9R0Q8, Q80T14, A7X406, A7X409, P20693, P25031, P28163, Q07108, Q25116, Q26646, Q6X5S5, A4KWA1, O54707, P10716, P27471, P27811, P27812, P27814, P49300, P60883, Q0ZUP0, Q0ZUP1, Q12918, Q13241, Q5NKN2, Q5NKN4, Q63378, Q67EQ1, Q8HXZ7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FREM1	“up-regulates quantity by expression”	NPNT	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1495 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	51
Uncertain significance	866
Likely benign	286
Benign	144

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1189034	NC_000009.12:g.(?14762351)(14792870_?)del	Pathogenic
1322938	NM_001379081.2(FREM1):c.4178-1G>A	Pathogenic
1322939	NM_001379081.2(FREM1):c.4375dup (p.Asp1459fs)	Pathogenic
1324428	NM_001379081.2(FREM1):c.1288C>T (p.Arg430Ter)	Pathogenic
1710689	NM_001379081.2(FREM1):c.4312C>T (p.Arg1438Ter)	Pathogenic
1988	NM_001379081.2(FREM1):c.2722del (p.Val908fs)	Pathogenic
2427316	NC_000009.11:g.(?14737394)(14868975_?)del	Pathogenic
2427317	NC_000009.11:g.(?14801630)(14859502_?)del	Pathogenic
2505948	NM_144966.5(FREM1):c.6139del	Pathogenic
2627749	NM_001379081.2(FREM1):c.870_876del (p.Pro291fs)	Pathogenic
2627750	NM_001379081.2(FREM1):c.2T>C (p.Met1Thr)	Pathogenic
2715524	NM_001379081.2(FREM1):c.3439G>T (p.Glu1147Ter)	Pathogenic
3061742	NM_001379081.2(FREM1):c.2722G>N (p.Val908Xaa)	Pathogenic
30763	NM_001379081.2(FREM1):c.2097_2100del (p.Lys699fs)	Pathogenic
3245399	NC_000009.11:g.(?14848643)(14868975_?)del	Pathogenic
3374900	NM_001379081.2(FREM1):c.3289A>T (p.Lys1097Ter)	Pathogenic
3631510	NM_001379081.2(FREM1):c.5490_5491insAGGG (p.Ser1831fs)	Pathogenic
3687755	NM_001379081.2(FREM1):c.2557del (p.Asp853fs)	Pathogenic
4279460	GRCh37/hg19 9p22.3(chr9:14812846-14860436)x1	Pathogenic
4293998	NM_001379081.2(FREM1):c.2626del (p.Val876fs)	Pathogenic
430003	NM_001379081.2(FREM1):c.3910G>T (p.Glu1304Ter)	Pathogenic
4700204	NM_001379081.2(FREM1):c.2891_2892del (p.Thr964fs)	Pathogenic
4723289	NM_001379081.2(FREM1):c.2136_2143dup (p.Ala715fs)	Pathogenic
4732017	NM_001379081.2(FREM1):c.5220G>A (p.Trp1740Ter)	Pathogenic
686211	GRCh37/hg19 9p22.3(chr9:14757743-14830372)x1	Pathogenic
68751	NM_001379081.2(FREM1):c.6271G>A (p.Val2091Ile)	Pathogenic
1066336	NM_001379081.2(FREM1):c.2641-1G>T	Likely pathogenic
1180853	NM_001379081.2(FREM1):c.3784A>T (p.Lys1262Ter)	Likely pathogenic
1324431	NM_001379081.2(FREM1):c.4992_4993insA (p.Asp1665fs)	Likely pathogenic
1496598	NM_001379081.2(FREM1):c.829-1G>C	Likely pathogenic

SpliceAI

7225 predictions. Top by Δscore:

Variant	Effect	Δscore
9:14747051:CC:C	acceptor_loss	1.0000
9:14747430:T:C	acceptor_gain	1.0000
9:14747440:C:CT	acceptor_gain	1.0000
9:14747441:A:T	acceptor_gain	1.0000
9:14747444:A:T	acceptor_gain	1.0000
9:14747447:C:CT	acceptor_gain	1.0000
9:14747448:A:T	acceptor_gain	1.0000
9:14747451:A:T	acceptor_gain	1.0000
9:14747453:CAA:C	acceptor_gain	1.0000
9:14747454:A:T	acceptor_gain	1.0000
9:14747676:CTTA:C	donor_loss	1.0000
9:14747677:TTA:T	donor_loss	1.0000
9:14747678:T:TG	donor_loss	1.0000
9:14747679:A:AC	donor_gain	1.0000
9:14747680:C:CC	donor_gain	1.0000
9:14750128:T:TA	donor_gain	1.0000
9:14750129:C:A	donor_gain	1.0000
9:14750272:CATTC:C	acceptor_gain	1.0000
9:14750398:TGC:T	donor_gain	1.0000
9:14759897:CCAAA:C	acceptor_gain	1.0000
9:14759898:CAAA:C	acceptor_gain	1.0000
9:14759898:CAAAC:C	acceptor_gain	1.0000
9:14759902:C:CC	acceptor_gain	1.0000
9:14759904:G:C	acceptor_gain	1.0000
9:14759906:G:C	acceptor_gain	1.0000
9:14759906:G:GC	acceptor_gain	1.0000
9:14759908:G:C	acceptor_gain	1.0000
9:14759908:G:GC	acceptor_gain	1.0000
9:14769722:A:AC	donor_gain	1.0000
9:14769723:C:CC	donor_gain	1.0000

AlphaMissense

14465 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:14759888:A:G	W1740R	0.990
9:14759888:A:T	W1740R	0.990
9:14823300:A:C	Y733D	0.990
9:14746963:C:G	C2033S	0.983
9:14746964:A:T	C2033S	0.983
9:14842612:A:T	V481D	0.982
9:14824877:A:G	L666P	0.981
9:14750181:C:G	A1835P	0.980
9:14842607:A:C	Y483D	0.980
9:14857642:A:C	Y247D	0.980
9:14737412:C:G	C2175S	0.979
9:14737413:A:T	C2175S	0.979
9:14851328:A:C	Y370D	0.978
9:14851362:G:C	F358L	0.978
9:14851362:G:T	F358L	0.978
9:14851364:A:G	F358L	0.978
9:14859303:A:G	C171R	0.978
9:14746382:C:A	W2075C	0.977
9:14746382:C:G	W2075C	0.977
9:14816870:A:C	Y850D	0.977
9:14823303:C:G	A732P	0.976
9:14824836:A:C	Y680D	0.976
9:14841570:G:C	F586L	0.976
9:14841570:G:T	F586L	0.976
9:14841572:A:G	F586L	0.976
9:14842577:C:G	D493H	0.976
9:14859302:C:G	C171S	0.976
9:14859303:A:T	C171S	0.976
9:14750144:A:G	I1847T	0.975
9:14841506:C:G	D608H	0.975

dbSNP variants (sampled 300 via entrez): RS1000006837 (9:14757757 G>C), RS1000014256 (9:14869589 C>A), RS1000039446 (9:14888445 G>A), RS1000044859 (9:14856695 T>C), RS1000047312 (9:14873595 T>C), RS1000064923 (9:14886258 G>A), RS1000074385 (9:14820838 G>A), RS1000095801 (9:14822408 C>T), RS1000118154 (9:14886045 G>A), RS1000118778 (9:14854108 T>A), RS1000125985 (9:14762366 C>T), RS1000152531 (9:14752820 A>G), RS1000179580 (9:14781250 T>A,C), RS1000215447 (9:14861126 T>A,C), RS1000216798 (9:14871944 T>C)

Disease associations

OMIM: gene MIM:608944 | disease phenotypes: MIM:608980, MIM:248450, MIM:614485, MIM:142340, MIM:604229, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
oculotrichoanal syndrome	Definitive	Autosomal recessive
trigonocephaly 2	Strong	Autosomal dominant
BNAR syndrome	Strong	Autosomal recessive
isolated trigonocephaly	Supportive	Autosomal dominant
renal agenesis, unilateral	Supportive	Autosomal dominant

Mondo (11): BNAR syndrome (MONDO:0012165), oculotrichoanal syndrome (MONDO:0009560), trigonocephaly 2 (MONDO:0013774), congenital diaphragmatic hernia (MONDO:0005711), Peters anomaly (MONDO:0011414), Rieger anomaly (MONDO:0019628), chronic kidney disease (MONDO:0005300), congenital anomaly of kidney and urinary tract (MONDO:0019719), microcephaly (MONDO:0001149), isolated trigonocephaly (MONDO:0018065), renal agenesis, unilateral (MONDO:0019636)

Orphanet (7): BNAR syndrome (Orphanet:217266), Oculotrichoanal syndrome (Orphanet:2717), Non-syndromic metopic craniosynostosis (Orphanet:3366), Congenital diaphragmatic hernia (Orphanet:2140), Peters anomaly (Orphanet:708), Rieger anomaly (Orphanet:91483), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000104	Renal agenesis
HP:0000122	Unilateral renal agenesis
HP:0000143	Rectovaginal fistula
HP:0000148	Vaginal atresia
HP:0000200	Short lingual frenulum
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000336	Prominent supraorbital ridges
HP:0000341	Narrow forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000456	Bifid nasal tip
HP:0000494	Downslanted palpebral fissures
HP:0000528	Anophthalmia
HP:0000568	Microphthalmia
HP:0000574	Thick eyebrow
HP:0000579	Nasolacrimal duct obstruction
HP:0000601	Hypotelorism
HP:0000625	Eyelid coloboma
HP:0000636	Upper eyelid coloboma
HP:0000664	Synophrys

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000522_13	Height	2.000000e-06
GCST004321_23	Facial morphology (factor 17, height of vermillion upper lip)	2.000000e-08
GCST004860_145	Alcoholic chronic pancreatitis	4.000000e-06
GCST008822_9	Neuritic plaque	9.000000e-08
GCST010482_3	Cardiovascular death or myocardial infarction in response to clopidogrel treatment	6.000000e-06
GCST012490_22	Femur bone mineral density x serum urate levels interaction	1.000000e-12
GCST012490_458	Femur bone mineral density x serum urate levels interaction	4.000000e-10
GCST90000050_62	Age at first birth	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006798	neuritic plaque measurement
EFO:0006919	cardiovascular event measurement
EFO:0004531	urate measurement
EFO:0009101	age at first birth measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567672	Bifid Nose With Or Without Anorectal And Renal Anomalies (supp.)
C566906	Cakut (supp.)
C536022	Marles Greenberg Persaud syndrome (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases methylation, increases mutagenesis, affects methylation, decreases expression	6
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	affects expression, affects cotreatment, increases methylation	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression, increases methylation	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
benzo(k)fluoranthene	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
benz(a)anthracene	decreases expression	1
benazol P	affects expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
belinostat	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Methapyrilene	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria