FREM2

Summary

FREM2 (FRAS1 related extracellular matrix 2, HGNC:25396) is a protein-coding gene on chromosome 13q13.3, encoding FRAS1-related extracellular matrix protein 2 (Q5SZK8). Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia.

This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome.

Source: NCBI Gene 341640 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fraser syndrome 2 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 2,506 total — 81 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 89
• MANE Select transcript: NM_207361

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25396
Approved symbol	FREM2
Name	FRAS1 related extracellular matrix 2
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp686J0811
Ensembl gene	ENSG00000150893
Ensembl biotype	protein_coding
OMIM	608945
Entrez	341640

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000280481, ENST00000482551

RefSeq mRNA: 1 — MANE Select: NM_207361 NM_207361

CCDS: CCDS31960

Canonical transcript exons

ENST00000280481 — 24 exons

Exon	Start	End
ENSE00001094051	38856126	38856256
ENSE00001094053	38864275	38864606
ENSE00001094057	38859287	38859590
ENSE00001094086	38861431	38861562
ENSE00001094088	38851686	38851868
ENSE00001094091	38857875	38858033
ENSE00001094092	38850944	38851108
ENSE00001165901	38878831	38878977
ENSE00001165906	38878134	38878321
ENSE00001165911	38877117	38877243
ENSE00001165915	38876248	38876382
ENSE00001165925	38876022	38876149
ENSE00001165934	38874482	38874586
ENSE00001165939	38872742	38872934
ENSE00001239598	38880284	38887131
ENSE00001293317	38784557	38784808
ENSE00001319366	38783070	38783195
ENSE00001481928	38769578	38769808
ENSE00001481930	38764304	38764450
ENSE00001481931	38697698	38697787
ENSE00001838441	38687077	38692517
ENSE00003574963	38846573	38846722
ENSE00003636743	38850038	38850235
ENSE00003684382	38848461	38848670

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 97.30.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2783 / max 132.7014, expressed in 425 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134804	0.9593	308
134805	0.7521	289
134803	0.5669	270

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.30	gold quality
kidney epithelium	UBERON:0004819	92.93	gold quality
renal medulla	UBERON:0000362	86.10	gold quality
oviduct epithelium	UBERON:0004804	85.70	gold quality
tibialis anterior	UBERON:0001385	82.07	gold quality
deltoid	UBERON:0001476	81.03	gold quality
epithelial cell of pancreas	CL:0000083	80.57	gold quality
kidney	UBERON:0002113	80.04	gold quality
metanephros	UBERON:0000081	78.83	gold quality
lower lobe of lung	UBERON:0008949	77.56	gold quality
adult mammalian kidney	UBERON:0000082	77.23	gold quality
vastus lateralis	UBERON:0001379	76.88	gold quality
quadriceps femoris	UBERON:0001377	76.39	gold quality
endometrium	UBERON:0001295	75.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.72	gold quality
skeletal muscle tissue	UBERON:0001134	75.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.70	gold quality
biceps brachii	UBERON:0001507	74.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	73.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.76	silver quality
muscle tissue	UBERON:0002385	71.42	gold quality
pigmented layer of retina	UBERON:0001782	70.70	gold quality
nasal cavity epithelium	UBERON:0005384	70.50	silver quality
body of pancreas	UBERON:0001150	69.99	gold quality
cortex of kidney	UBERON:0001225	69.56	gold quality
thyroid gland	UBERON:0002046	68.95	gold quality
metanephros cortex	UBERON:0010533	68.87	gold quality
pancreas	UBERON:0001264	68.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	68.62	gold quality
right lobe of thyroid gland	UBERON:0001119	67.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	83.76
E-ANND-3	yes	11.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TFAP2A, TFAP2C

miRNA regulators (miRDB)

260 targeting FREM2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-190A-3P	100.00	80.35	5520
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-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367

Literature-anchored findings (GeneRIF, showing 11)

• report on 2 fetuses affected by Fraser syndrome (FS); a homozygous IVS14 + 1G – A mutation in FREM2 was indentified; present report provides additional evidence that FS may be caused by complete or near-complete lack or loss of function of FREM2 protein (PMID:18203166)
• 1 new mutation in FREM2 was identified in families with Fraser syndrome. (PMID:18671281)
• Heterozygous missense mutations in FREM2 cause non-syndromic congenital abnormalities of the kidney and urinary tract in humans. (PMID:21900877)
• Amplification of the FREM2 gene is associated with mesenchymal differentiation in gliosarcoma. (PMID:22538188)
• 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)
• Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing Congenital diaphragmatic hernia (CDH) and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression (PMID:29618029)
• 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)
• FREM2 is thus proposed as a novel GB biomarker and a putative biomarker of glioblastoma stem cells. Both FREM2 and SPRY1 are expressed on the surface of the GB cells, while SPRY1 alone was found overexpressed in the cytosol of non-malignant astrocytes. (PMID:29734672)
• Our findings extend the spectrum of FREM2 mutations, and provide insights into opportunities for the prenatal diagnosis of isolated cryptophthalmos. Furthermore, our work highlights the importance of the FREM2 protein during the development of eyelids and the anterior segment of the eyeballs, establishes a suitable animal model for studying epithelial reopening during eyelid development and serves as a valuable reference (PMID:30802441)
• Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families. (PMID:32643034)
• Targeted resequencing of the 13q13 spondyloarthritis-linked locus identifies a rare variant in FREM2 possibly associated with familial spondyloarthritis. (PMID:35640836)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	frem2a	ENSDARG00000076856
danio_rerio	frem2b	ENSDARG00000102626
mus_musculus	Frem2	ENSMUSG00000037016
rattus_norvegicus	Frem2	ENSRNOG00000021670

Paralogs (7): SLC8A3 (ENSG00000100678), SLC8A2 (ENSG00000118160), FRAS1 (ENSG00000138759), ADGRV1 (ENSG00000164199), FREM1 (ENSG00000164946), SLC8A1 (ENSG00000183023), FREM3 (ENSG00000183090)

Protein

Protein identifiers

FRAS1-related extracellular matrix protein 2 — Q5SZK8 (reviewed: Q5SZK8)

Alternative names: ECM3 homolog

All UniProt accessions (1): Q5SZK8

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia. Required for epidermal adhesion. Involved in the development of eyelids and the anterior segment of the eyeballs.

Subunit / interactions. Interacts with FREM1.

Subcellular location. Cell membrane.

Disease relevance. Fraser syndrome 2 (FRASRS2) [MIM:617666] A form of Fraser syndrome, an autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, and urogenital abnormalities including renal agenesis or hypoplasia. Additional features include abnormalities of the larynx, ear malformations, and facial abnormalities. The disease is caused by variants affecting the gene represented in this entry. Cryptophthalmos, unilateral or bilateral, isolated (CRYPTOP) [MIM:123570] An autosomal dominant, rare condition characterized by congenital eyelid malformation with an underlying malformed eye. It can be bilateral or unilateral and is classified into complete (typical), incomplete (atypical) and abortive (congenital symblepharon) forms. The skin of patients with complete cryptophthalmos extends uninterrupted from the forehead to the cheek, whereas incomplete cryptophthalmos exists when there is medial eyelid fusion, but coincident intact lateral structures. The symblepharon variety presents with fusion of the upper eyelid skin to the superior aspect of the globe. The complete variety is the most common form. The disease is caused by variants affecting the gene represented in this entry.

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

Similarity. Belongs to the FRAS1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5SZK8-1	1	yes
Q5SZK8-2	2

RefSeq proteins (1): NP_997244* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003644	Calx_beta	Domain
IPR038081	CalX-like_sf	Homologous_superfamily
IPR039005	CSPG_rpt	Repeat
IPR045658	FRAS1-rel_N	Domain
IPR051561	FRAS1_ECM	Family

Pfam: PF03160, PF16184, PF19309

UniProt features (63 total): sequence variant 18, repeat 12, sequence conflict 11, domain 5, glycosylation site 5, region of interest 3, topological domain 2, compositionally biased region 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q5SZK8 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Glycosylation sites (5): 358, 1244, 1369, 1584, 1741

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 298 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, chr13q13, GOBP_EAR_DEVELOPMENT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_APPENDAGE_DEVELOPMENT, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_EMBRYO_DEVELOPMENT, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOCC_BASEMENT_MEMBRANE, GOBP_EPITHELIAL_STRUCTURE_MAINTENANCE, GOBP_CELL_SUBSTRATE_ADHESION, GOBP_CELL_MATRIX_ADHESION, GOBP_TISSUE_MORPHOGENESIS

GO Biological Process (9): eye development (GO:0001654), kidney development (GO:0001822), morphogenesis of an epithelium (GO:0002009), cell communication (GO:0007154), cell adhesion (GO:0007155), heart development (GO:0007507), anatomical structure morphogenesis (GO:0009653), embryonic digit morphogenesis (GO:0042733), inner ear development (GO:0048839)

GO Molecular Function (2): metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (4): basement membrane (GO:0005604), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	2
cellular process	2
anatomical structure development	2
sensory organ development	1
visual system development	1
renal system development	1
tissue morphogenesis	1
epithelium development	1
circulatory system development	1
developmental process	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
ear development	1
cation binding	1
binding	1
extracellular matrix	1
membrane	1
cell periphery	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FREM2	FREM1	Q5H8C1	917
FREM2	FRAS1	Q86XX4	901
FREM2	GRIP1	Q9Y3R0	874
FREM2	TRPC4	Q9UBN4	609
FREM2	TCF12	Q99081	588
FREM2	PROSER1	Q86XN7	497
FREM2	VWA2	Q5GFL6	476
FREM2	DSCAM	O60469	449
FREM2	AMZ1	Q400G9	447
FREM2	HMCN1	Q96RW7	435
FREM2	CCDC57	Q2TAC2	429
FREM2	NRXN1	Q9ULB1	429
FREM2	OR4D9	Q8NGE8	428
FREM2	MAPK8IP3	Q9UPT6	427
FREM2	FASTKD3	Q14CZ7	426

IntAct

42 interactions, top by confidence:

A	B	Type	Score
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
INSL6	POTEF	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
PDGFB	DKC1	psi-mi:“MI:0914”(association)	0.530
POLR2A	URI1	psi-mi:“MI:0914”(association)	0.530
FREM2	HNRNPA1	psi-mi:“MI:0915”(physical association)	0.400
FREM2	HNRNPCL2	psi-mi:“MI:0915”(physical association)	0.400
FREM2	FREM1	psi-mi:“MI:0915”(physical association)	0.400
TRAF2	UMAD1	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	FAM234B	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
ADAMTS13	C2CD4B	psi-mi:“MI:0914”(association)	0.350
C2CD4B	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
MRPS17	POLRMT	psi-mi:“MI:0914”(association)	0.350
TRIM68	BTN3A3	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
FCGR1A	PCDH17	psi-mi:“MI:0914”(association)	0.350
CXCL16	SCAMP1	psi-mi:“MI:0914”(association)	0.350
TIMP3	DDX3Y	psi-mi:“MI:0914”(association)	0.350
ZBBX	ZZEF1	psi-mi:“MI:0914”(association)	0.350
NXPH2	B4GALT5	psi-mi:“MI:0914”(association)	0.350
UCN3	PCDH7	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A6H8M9, D3YX43, O08644, O15197, O55134, O70394, O70540, O75309, O88338, P0C091, P0C0K6, P0C0K7, P0DP72, P21709, P40223, P59862, P70289, Q00657, Q04912, Q0V8J4, Q28634, Q501P1, Q53RD9, Q58Y75, Q5DRE2, Q5H8B9, Q5R6F5, Q5SZK8, Q60750, Q63315, Q64612, Q6MG64, Q6NVD0, Q6PFX6, Q6UVK1, Q76MJ5, Q7TN88, Q7Z442, Q86UP0

Diamond homologs: P0C091, Q5H8B9, Q5H8C1, Q5SZK8, Q684R7, Q6NVD0, Q86XX4, Q9GV77, Q9VDG5, Q95J96, Q95LC6, Q9R0Q8, Q80T14, A7X406, A7X409, P20693, P25031, P28163, Q07108, Q25116, Q26646, Q6X5S5, A1A5Y0, P23685, P48765, P48766, P48767, P57103, P70414, P70549, Q01728, Q2KIT5, Q3UQ28, Q4G063, Q4V7M2, Q5XH36, Q60438, Q63415, Q6P4Z2, Q6UXH1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2506 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	41
Uncertain significance	1048
Likely benign	1029
Benign	145

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322941	NM_207361.6(FREM2):c.4396C>T (p.Arg1466Ter)	Pathogenic
1322942	NM_207361.6(FREM2):c.3955dup (p.Thr1319fs)	Pathogenic
1408187	NM_207361.6(FREM2):c.6386dup (p.Met2130fs)	Pathogenic
1926925	NM_207361.6(FREM2):c.8533C>T (p.Arg2845Ter)	Pathogenic
1986	NM_207361.6(FREM2):c.7519+1G>A	Pathogenic
2583092	NM_207361.6(FREM2):c.2689C>T (p.Gln897Ter)	Pathogenic
2691573	NM_207361.6(FREM2):c.8451dup (p.Cys2818fs)	Pathogenic
2692628	NM_207361.6(FREM2):c.2533del (p.His845fs)	Pathogenic
2695829	NM_207361.6(FREM2):c.4225del (p.Tyr1409fs)	Pathogenic
2704692	NM_207361.6(FREM2):c.5274_5278del (p.Lys1758fs)	Pathogenic
2708455	NM_207361.6(FREM2):c.3691C>T (p.Gln1231Ter)	Pathogenic
2713043	NM_207361.6(FREM2):c.5751_5754del (p.Cys1918fs)	Pathogenic
2724025	NM_207361.6(FREM2):c.4527del (p.Gln1510fs)	Pathogenic
2729631	NM_207361.6(FREM2):c.6058del (p.Asp2020fs)	Pathogenic
2743439	NM_207361.6(FREM2):c.7060_7066del (p.Thr2354fs)	Pathogenic
2747163	NM_207361.6(FREM2):c.4501G>T (p.Glu1501Ter)	Pathogenic
2757384	NM_207361.6(FREM2):c.1675C>T (p.Gln559Ter)	Pathogenic
2760291	NM_207361.6(FREM2):c.837G>A (p.Trp279Ter)	Pathogenic
2762927	NM_207361.6(FREM2):c.349C>T (p.Gln117Ter)	Pathogenic
2767069	NM_207361.6(FREM2):c.2735_2741del (p.Asp912fs)	Pathogenic
2768640	NM_207361.6(FREM2):c.2788dup (p.Arg930fs)	Pathogenic
2770429	NM_207361.6(FREM2):c.6597C>A (p.Cys2199Ter)	Pathogenic
2778637	NM_207361.6(FREM2):c.5917G>T (p.Glu1973Ter)	Pathogenic
2784297	NM_207361.6(FREM2):c.5960dup (p.Arg1988fs)	Pathogenic
2785026	NM_207361.6(FREM2):c.264_265delinsAA (p.Trp88_Leu89delinsTer)	Pathogenic
2786027	NM_207361.6(FREM2):c.1231G>T (p.Glu411Ter)	Pathogenic
2799204	NM_207361.6(FREM2):c.2425C>T (p.Arg809Ter)	Pathogenic
2803781	NM_207361.6(FREM2):c.187del (p.Ala63fs)	Pathogenic
2816727	NM_207361.6(FREM2):c.905_906del (p.His302fs)	Pathogenic
2819410	NM_207361.6(FREM2):c.6716_6717del (p.Leu2239fs)	Pathogenic

SpliceAI

3825 predictions. Top by Δscore:

Variant	Effect	Δscore
13:38764295:A:AG	acceptor_gain	1.0000
13:38764296:T:G	acceptor_gain	1.0000
13:38764300:CAAG:C	acceptor_loss	1.0000
13:38764301:A:AG	acceptor_gain	1.0000
13:38764301:AAG:A	acceptor_gain	1.0000
13:38764301:AAGGT:A	acceptor_gain	1.0000
13:38764302:A:G	acceptor_gain	1.0000
13:38764302:AGGT:A	acceptor_gain	1.0000
13:38764303:G:GA	acceptor_loss	1.0000
13:38764303:G:GC	acceptor_gain	1.0000
13:38764303:GGT:G	acceptor_gain	1.0000
13:38764303:GGTG:G	acceptor_gain	1.0000
13:38764446:TATAA:T	donor_gain	1.0000
13:38764447:ATAA:A	donor_gain	1.0000
13:38764448:TAA:T	donor_gain	1.0000
13:38764448:TAAG:T	donor_loss	1.0000
13:38764449:AA:A	donor_gain	1.0000
13:38764449:AAGTA:A	donor_loss	1.0000
13:38764450:AGTA:A	donor_loss	1.0000
13:38764451:G:GG	donor_gain	1.0000
13:38764451:G:T	donor_loss	1.0000
13:38764452:TAAG:T	donor_loss	1.0000
13:38769805:GATG:G	donor_gain	1.0000
13:38783068:A:AG	acceptor_gain	1.0000
13:38783069:G:GA	acceptor_gain	1.0000
13:38783069:GA:G	acceptor_gain	1.0000
13:38783176:G:GA	donor_gain	1.0000
13:38784548:T:A	acceptor_gain	1.0000
13:38784553:CCA:C	acceptor_loss	1.0000
13:38784555:A:AG	acceptor_gain	1.0000

AlphaMissense

20839 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:38858025:T:C	C2403R	0.999
13:38859374:T:A	W2435R	0.999
13:38859374:T:C	W2435R	0.999
13:38864361:T:A	C2580S	0.999
13:38864361:T:C	C2580R	0.999
13:38864362:G:C	C2580S	0.999
13:38864532:T:A	W2637R	0.999
13:38864532:T:C	W2637R	0.999
13:38864534:G:C	W2637C	0.999
13:38864534:G:T	W2637C	0.999
13:38876126:T:A	W2796R	0.999
13:38876126:T:C	W2796R	0.999
13:38880302:T:A	W3009R	0.999
13:38880302:T:C	W3009R	0.999
13:38692011:T:C	L1556P	0.998
13:38856216:T:A	V2339D	0.998
13:38858026:G:A	C2403Y	0.998
13:38858027:T:G	C2403W	0.998
13:38859376:G:C	W2435C	0.998
13:38859376:G:T	W2435C	0.998
13:38859509:T:C	C2480R	0.998
13:38859560:A:C	S2497R	0.998
13:38859562:C:A	S2497R	0.998
13:38859562:C:G	S2497R	0.998
13:38864365:C:T	S2581F	0.998
13:38864369:C:A	N2582K	0.998
13:38864369:C:G	N2582K	0.998
13:38864566:T:C	L2648P	0.998
13:38864577:T:C	C2652R	0.998
13:38864578:G:A	C2652Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000004374 (13:38695669 T>C), RS1000020863 (13:38876528 G>A,C), RS1000044181 (13:38795641 C>T), RS1000052996 (13:38750014 A>G), RS1000095412 (13:38883939 G>T), RS1000096503 (13:38801981 C>T), RS1000104280 (13:38794131 G>T), RS1000144138 (13:38724884 A>T), RS1000146815 (13:38792003 A>G), RS1000150805 (13:38729319 T>C), RS1000153082 (13:38873250 A>C), RS1000165764 (13:38859868 T>A), RS1000177134 (13:38725213 A>G), RS1000202724 (13:38840707 C>G), RS1000207168 (13:38713255 G>A,T)

Disease associations

OMIM: gene MIM:608945 | disease phenotypes: MIM:617666, MIM:123570, MIM:219000, MIM:610805, MIM:181500, MIM:142340, MIM:616487

GenCC curated gene-disease

Disease	Classification	Inheritance
Fraser syndrome 2	Definitive	Autosomal recessive
Fraser syndrome 1	Strong	Autosomal recessive
Fraser syndrome	Supportive	Autosomal recessive
renal agenesis, unilateral	Supportive	Autosomal dominant

Mondo (13): Fraser syndrome 2 (MONDO:0054738), isolated cryptophthalmia (MONDO:0007410), Fraser syndrome 1 (MONDO:0054737), congenital anomaly of kidney and urinary tract (MONDO:0019719), prostate cancer (MONDO:0008315), schizophrenia (MONDO:0005090), childhood-onset schizophrenia (MONDO:0957430), microcephaly (MONDO:0001149), congenital diaphragmatic hernia (MONDO:0005711), epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661), renal agenesis, unilateral (MONDO:0019636), cryptophthalmia (MONDO:0020153), Fraser syndrome (MONDO:0009046)

Orphanet (9): Fraser syndrome (Orphanet:2052), Isolated cryptophthalmia (Orphanet:91396), Renal or urinary tract malformation (Orphanet:93545), Familial prostate cancer (Orphanet:1331), Childhood-onset schizophrenia (Orphanet:641496), Congenital diaphragmatic hernia (Orphanet:2140), Renal agenesis, unilateral (Orphanet:93100), Cryptophthalmia (Orphanet:98562), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000079	Abnormality of the urinary system
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000122	Unilateral renal agenesis
HP:0000142	Abnormal vagina morphology
HP:0000148	Vaginal atresia
HP:0000160	Narrow mouth
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000370	Abnormality of the middle ear
HP:0000377	Abnormal pinna morphology
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000470	Short neck

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001272_6	Cytomegalovirus antibody response	7.000000e-06
GCST003026_3	Yu-Zhi constitution type in type 2 diabetes	2.000000e-06
GCST006988_16	Blond vs. brown/black hair color	1.000000e-10
GCST010320_92	PR interval	4.000000e-09
GCST010321_80	PR interval	4.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007638	Yu-Zhi constitution type
EFO:0003924	hair color
EFO:0004462	PR interval

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D058497	Fraser Syndrome	C05.116.099.370.894.819.428; C05.660.585.800.428; C05.660.906.819.428; C11.250.390; C12.050.351.875.397; C12.200.706.410; C12.800.410; C16.131.077.371; C16.131.384.442; C16.131.621.585.800.428; C16.131.621.906.819.428; C16.131.939.410
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C566906	Cakut (supp.)
C565138	Cryptophthalmos, Unilateral or Bilateral, Isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	8
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation, increases mutagenesis	4
methylmercuric chloride	decreases expression	3
trichostatin A	affects cotreatment, increases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Nickel	decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
chloroacetaldehyde	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
perfluoro-n-nonanoic acid	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
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Cidofovir	decreases expression	1
Ethanol	increases expression	1
Cisplatin	decreases expression	1
Clodronic Acid	decreases expression	1
Hydrogen Peroxide	increases expression	1
Methapyrilene	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Oxygen	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer