FRAS1

Summary

FRAS1 (Fraser extracellular matrix complex subunit 1, HGNC:19185) is a protein-coding gene on chromosome 4q21.21, encoding Extracellular matrix organizing protein FRAS1 (Q86XX4). Involved in extracellular matrix organization.

This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 80144 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fraser syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 3,613 total — 170 pathogenic, 124 likely-pathogenic
• Phenotypes (HPO): 104
• MANE Select transcript: NM_025074

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19185
Approved symbol	FRAS1
Name	Fraser extracellular matrix complex subunit 1
Location	4q21.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22031, FLJ14927, KIAA1500
Ensembl gene	ENSG00000138759
Ensembl biotype	protein_coding
OMIM	607830
Entrez	80144

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000325942, ENST00000502446, ENST00000508900, ENST00000508909, ENST00000510944, ENST00000512123, ENST00000682513, ENST00000682583, ENST00000683711, ENST00000684159, ENST00000915768

RefSeq mRNA: 2 — MANE Select: NM_025074 NM_001166133, NM_025074

CCDS: CCDS54771, CCDS54772

Canonical transcript exons

ENST00000512123 — 74 exons

Exon	Start	End
ENSE00000725901	78519331	78519481
ENSE00000725911	78521523	78521630
ENSE00000725936	78513392	78513552
ENSE00000726042	78536995	78537200
ENSE00000935647	78515799	78516013
ENSE00000935648	78522649	78522808
ENSE00001025452	78441162	78441297
ENSE00001025457	78438570	78438718
ENSE00001025461	78445522	78445712
ENSE00001025467	78438902	78439064
ENSE00001025473	78526541	78526657
ENSE00001077992	78374111	78374251
ENSE00001139872	78539294	78539440
ENSE00001139889	78534449	78534615
ENSE00001140282	78475438	78475606
ENSE00001140384	78315594	78315734
ENSE00001192709	78282820	78282967
ENSE00001192713	78281398	78281433
ENSE00001192718	78278655	78278744
ENSE00001268062	78507421	78507608
ENSE00001268079	78496805	78496961
ENSE00001268114	78508731	78509006
ENSE00001268131	78499721	78499921
ENSE00001268179	78511274	78511506
ENSE00001268187	78477815	78478061
ENSE00001272503	78418949	78419063
ENSE00001272563	78372718	78372858
ENSE00001272623	78337674	78337817
ENSE00001272785	78286405	78286539
ENSE00001272790	78284405	78284548
ENSE00001291584	78308066	78308209
ENSE00001294973	78318810	78318986
ENSE00001316805	78317368	78317508
ENSE00001318359	78333272	78333412
ENSE00001331024	78488875	78489080
ENSE00001331025	78482388	78482535
ENSE00001331026	78481804	78481964
ENSE00001331028	78473438	78473597
ENSE00001331029	78472180	78472330
ENSE00001331031	78469978	78470091
ENSE00001331033	78466208	78466435
ENSE00001331035	78464443	78464583
ENSE00001331036	78464021	78464145
ENSE00001331037	78452175	78452354
ENSE00001331038	78451772	78451891
ENSE00001331039	78450151	78450339
ENSE00001331042	78448053	78448316
ENSE00001331043	78446727	78446880
ENSE00001331051	78421863	78422000
ENSE00001331053	78412969	78413085
ENSE00001331055	78407663	78407841
ENSE00001331056	78400734	78400887
ENSE00001331058	78387375	78387701
ENSE00001331060	78384059	78384143
ENSE00001331062	78379726	78379996
ENSE00001331064	78375739	78375879
ENSE00001331070	78369838	78369984
ENSE00001331074	78363908	78364054
ENSE00001331076	78363513	78363665
ENSE00001331136	78255242	78255375
ENSE00001331138	78252392	78252551
ENSE00001331139	78245233	78245325
ENSE00001331141	78237510	78237617
ENSE00001331143	78065985	78066016
ENSE00001340953	78479374	78479718
ENSE00001358081	78540531	78544269
ENSE00001358351	78432357	78432604
ENSE00001358355	78430292	78430417
ENSE00001358548	78267241	78267432
ENSE00001358550	78266834	78266935
ENSE00001358552	78265025	78265108
ENSE00002448931	78424388	78424420
ENSE00002509738	78429095	78429226
ENSE00003848192	78057323	78058085

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6547 / max 154.6931, expressed in 993 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48432	3.1046	799
48434	1.3230	588
48430	0.9346	427
48431	0.1674	74
48433	0.0848	44
203259	0.0402	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	98.00	gold quality
parietal pleura	UBERON:0002400	94.98	gold quality
renal medulla	UBERON:0000362	93.38	gold quality
pleura	UBERON:0000977	90.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.13	gold quality
visceral pleura	UBERON:0002401	86.34	gold quality
middle temporal gyrus	UBERON:0002771	86.10	gold quality
lateral nuclear group of thalamus	UBERON:0002736	85.91	gold quality
colonic epithelium	UBERON:0000397	83.70	gold quality
placenta	UBERON:0001987	81.69	gold quality
biceps brachii	UBERON:0001507	79.97	gold quality
endothelial cell	CL:0000115	79.38	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.81	gold quality
esophagus squamous epithelium	UBERON:0006920	78.44	gold quality
adult organism	UBERON:0007023	78.29	gold quality
thyroid gland	UBERON:0002046	78.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	77.73	silver quality
left lobe of thyroid gland	UBERON:0001120	77.16	gold quality
endometrium	UBERON:0001295	76.68	gold quality
adult mammalian kidney	UBERON:0000082	76.54	gold quality
right lobe of thyroid gland	UBERON:0001119	76.17	gold quality
primary visual cortex	UBERON:0002436	75.81	gold quality
kidney	UBERON:0002113	75.57	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.14	silver quality
epithelial cell of pancreas	CL:0000083	74.71	gold quality
epithelium of esophagus	UBERON:0001976	73.99	gold quality
pancreatic ductal cell	CL:0002079	73.77	silver quality
cortical plate	UBERON:0005343	73.71	gold quality
palpebral conjunctiva	UBERON:0001812	73.66	gold quality
metanephros cortex	UBERON:0010533	73.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	58.08
E-CURD-119	yes	38.49
E-ANND-3	yes	8.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting FRAS1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-5189-3P	97.52	66.33	487
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-4313	97.18	63.15	420
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-4750-3P	96.65	64.38	512
HSA-MIR-4680-5P	96.43	67.15	893
HSA-MIR-4330	95.44	66.39	993

Literature-anchored findings (GeneRIF, showing 15)

• Locus FS1 at chromosome 4q21 is associated with Fraser syndrome. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) protein found in sea urchin. (PMID:12766769)
• In this review, recent studies support direct interactions between Fras1 and Frem proteins and shed new light on their role in the regulation of epidermal-basement membrane adhesion and organogenesis during development. (PMID:17654118)
• Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxhyl tail of Fras1. (PMID:18155042)
• 11 new mutations in FRAS1 were identified in families with Fraser syndrome. (PMID:18671281)
• Heterozygous missense mutations in FRAS1 cause non-syndromic congenital abnormalities of the kidney and urinary tract in humans. (PMID:21900877)
• molecular, clinical findings of 4 fetuses with Fraser syndrome from 2 families; in family one, found nonsense mutation (c.3730C>T, p.R1244X) previously described; in family 2 found a novel nonsense mutation previously not known (c.370C>T, p.R124X) (PMID:22029163)
• Analysis of FRAS1 and STRA6 mutations in the same family with eye anomalies. (PMID:22283518)
• First case of a family with two patients affected by Fraser syndrome due to a deletion of 64 kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene. (PMID:23473829)
• 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)
• Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer. (PMID:31597194)
• Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene. (PMID:31999076)
• Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families. (PMID:32643034)
• A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer. (PMID:33956343)
• DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway. (PMID:39367995)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fras1	ENSMUSG00000034687
rattus_norvegicus	Fras1	ENSRNOG00000002053

Paralogs (7): SLC8A3 (ENSG00000100678), SLC8A2 (ENSG00000118160), FREM2 (ENSG00000150893), ADGRV1 (ENSG00000164199), FREM1 (ENSG00000164946), SLC8A1 (ENSG00000183023), FREM3 (ENSG00000183090)

Protein

Protein identifiers

Extracellular matrix organizing protein FRAS1 — Q86XX4 (reviewed: Q86XX4)

Alternative names: Fraser syndrome 1 protein

All UniProt accessions (6): Q86XX4, A0A804HI32, A0A804HL50, H0Y8V2, H0Y9A6, H0Y9C9

UniProt curated annotations — full annotation on UniProt →

Function. Involved in extracellular matrix organization. Required for the regulation of epidermal-basement membrane adhesion responsible for proper organogenesis during embryonic development. Involved in brain organization and function.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in many adult tissues, with highest levels in kidney, pancreas and thalamus. Relatively high expression was also detected in fetal kidney and heart.

Disease relevance. Fraser syndrome 1 (FRASRS1) [MIM:219000] 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.

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 (5)

UniProt ID	Names	Canonical?
Q86XX4-1	1	yes
Q86XX4-2	2
Q86XX4-4	4
Q86XX4-5	5
Q86XX4-6	6

RefSeq proteins (2): NP_001159605, NP_079350* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001007	VWF_dom	Domain
IPR003644	Calx_beta	Domain
IPR006212	Furin_repeat	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR038081	CalX-like_sf	Homologous_superfamily
IPR039005	CSPG_rpt	Repeat
IPR051561	FRAS1_ECM	Family

Pfam: PF00093, PF03160, PF16184

UniProt features (87 total): repeat 26, glycosylation site 17, sequence variant 16, domain 11, splice variant 11, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q86XX4 — 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.

Post-translational modifications (1): 344

Glycosylation sites (17): 361, 728, 1093, 1108, 1504, 1777, 1948, 1978, 2563, 2664, 2682, 2908, 2985, 3070, 3218, 3676, 3875

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 388 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, GOZGIT_ESR1_TARGETS_DN, AP4_Q6, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CAGCTG_AP4_Q5, GTGCCTT_MIR506, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, GOBP_APPENDAGE_DEVELOPMENT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, ZIC1_01

GO Biological Process (10): morphogenesis of an epithelium (GO:0002009), metanephros morphogenesis (GO:0003338), cell communication (GO:0007154), anatomical structure morphogenesis (GO:0009653), protein transport (GO:0015031), embryonic limb morphogenesis (GO:0030326), skin development (GO:0043588), roof of mouth development (GO:0060021), animal organ development (GO:0048513), system development (GO:0048731)

GO Molecular Function (3): extracellular matrix structural constituent (GO:0005201), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (5): basement membrane (GO:0005604), plasma membrane (GO:0005886), collagen trimer (GO:0005581), membrane (GO:0016020), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
extracellular matrix	2
tissue morphogenesis	1
epithelium development	1
metanephros development	1
kidney morphogenesis	1
cellular process	1
developmental process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
animal organ development	1
multicellular organism development	1
structural molecule activity	1
cation binding	1
binding	1
membrane	1
cell periphery	1
protein-containing complex	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

2290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRAS1	FREM1	Q5H8C1	931
FRAS1	FREM2	Q5SZK8	901
FRAS1	GRIP1	Q9Y3R0	861
FRAS1	HMCN1	Q96RW7	679
FRAS1	TCF12	Q99081	565
FRAS1	EYA1	Q99502	444
FRAS1	SPATA25	Q9BR10	441
FRAS1	MAPK8IP3	Q9UPT6	441
FRAS1	VWF	P04275	437
FRAS1	PRSS57	Q6UWY2	435
FRAS1	FURIN	P09958	434
FRAS1	FAM163A	Q96GL9	428
FRAS1	EVC2	Q86UK5	425
FRAS1	MFSD12	Q6NUT3	420
FRAS1	HSPA5	P11021	413

IntAct

116 interactions, top by confidence:

A	B	Type	Score
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
QPCT	FRAS1	psi-mi:“MI:0915”(physical association)	0.560
BCOR	CBX4	psi-mi:“MI:0914”(association)	0.530
MGAT4C	GXYLT2	psi-mi:“MI:0914”(association)	0.530
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
GPHA2	PLXNA2	psi-mi:“MI:0914”(association)	0.530
LRRC4C	DVL2	psi-mi:“MI:0914”(association)	0.530
PRG3	ZNF324	psi-mi:“MI:0914”(association)	0.530
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530

BioGRID (146): FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM12, A1A5Y0, A2VCU8, A6BM72, A6QR11, E9QJQ6, O42182, O70534, O88281, P23142, P35555, P35953, P80370, P97607, P98133, P98155, P98156, P98165, P98166, Q08879, Q09163, Q28832, Q2VWQ2, Q5R3Z7, Q5VY43, Q61220, Q61554, Q61555, Q62918, Q62919, Q6DIB5, Q7ZXL5, Q80T14, Q80T91, Q80V70, Q86XX4, Q8C088, Q8R4Y4, Q8VIK5, Q90827

Diamond homologs: A0A6I8RMG7, A2AJ76, B3EWY9, B5DFC9, O35568, O77469, O88322, P10493, P14543, P41413, P48960, P98095, Q04592, Q09165, Q14112, Q19267, Q2KIT5, Q2Q421, Q2Q426, Q4G063, Q4V7F2, Q4V7M2, Q5EA46, Q5RBP1, Q5XH36, Q60438, Q6UXH1, Q6UXI9, Q7SXF6, Q7ZXL5, Q86XX4, Q8BPB5, Q8K4G1, Q8R4U0, Q8R4Y4, Q91XD7, Q96HD1, Q96RW7, Q9CYA0, Q9JJS0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Extracellular matrix organization	9	6.6×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
extracellular matrix disassembly	5	14.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3613 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	170
Likely pathogenic	124
Uncertain significance	1290
Likely benign	1543
Benign	144

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065638	NM_025074.7(FRAS1):c.6202A>T (p.Lys2068Ter)	Pathogenic
1074280	NM_025074.7(FRAS1):c.6805C>T (p.Arg2269Ter)	Pathogenic
1179032	NM_025074.7(FRAS1):c.7254dup (p.Glu2419fs)	Pathogenic
1179131	NM_025074.7(FRAS1):c.364del (p.Glu122fs)	Pathogenic
1188275	NM_025074.7(FRAS1):c.7966_7967del (p.Leu2656fs)	Pathogenic
1322936	NM_025074.7(FRAS1):c.2692del (p.His898fs)	Pathogenic
1328410	NM_025074.7(FRAS1):c.879C>G (p.Tyr293Ter)	Pathogenic
1328421	NM_025074.7(FRAS1):c.1176C>G (p.Tyr392Ter)	Pathogenic
1328427	NM_025074.7(FRAS1):c.7747C>T (p.Gln2583Ter)	Pathogenic
1332873	NM_025074.7(FRAS1):c.3293-2A>T	Pathogenic
1341530	NM_025074.7(FRAS1):c.5166del (p.Val1723fs)	Pathogenic
1451666	NM_025074.7(FRAS1):c.4197del (p.Asp1399fs)	Pathogenic
1705727	NM_025074.7(FRAS1):c.2376del (p.Ser793fs)	Pathogenic
1939018	NM_025074.7(FRAS1):c.4016G>A (p.Trp1339Ter)	Pathogenic
196043	NM_025074.7(FRAS1):c.3370dup (p.Ser1124fs)	Pathogenic
197861	NM_025074.7(FRAS1):c.370C>T (p.Arg124Ter)	Pathogenic
2006581	NM_025074.7(FRAS1):c.275del (p.Pro92fs)	Pathogenic
2033220	NM_025074.7(FRAS1):c.2776del (p.Arg926fs)	Pathogenic
2066374	NM_025074.7(FRAS1):c.5999_6000delinsC (p.Lys2000fs)	Pathogenic
2115539	NM_025074.7(FRAS1):c.1174del (p.Tyr392fs)	Pathogenic
219182	NM_025074.7(FRAS1):c.10287del (p.Leu3428_Tyr3429insTer)	Pathogenic
219183	NM_025074.7(FRAS1):c.5664_5665+19delinsT	Pathogenic
2441786	NM_025074.7(FRAS1):c.8922del (p.Asp2975fs)	Pathogenic
2628778	NM_025074.7(FRAS1):c.10597C>T (p.Arg3533Ter)	Pathogenic
2693329	NM_025074.7(FRAS1):c.5896dup (p.Leu1966fs)	Pathogenic
2694006	NM_025074.7(FRAS1):c.4065dup (p.Glu1356fs)	Pathogenic
2696884	NM_025074.7(FRAS1):c.2575delA (p.Lys859fs)	Pathogenic
2697557	NM_025074.7(FRAS1):c.95del (p.Asp32fs)	Pathogenic
2701300	NM_025074.7(FRAS1):c.10677_10680del (p.Pro3560fs)	Pathogenic
2706507	NM_025074.7(FRAS1):c.4110_4119dup (p.Pro1374fs)	Pathogenic

SpliceAI

13200 predictions. Top by Δscore:

Variant	Effect	Δscore
4:78058083:AAGG:A	donor_loss	1.0000
4:78058084:AGGTG:A	donor_loss	1.0000
4:78058087:T:A	donor_loss	1.0000
4:78175309:T:A	acceptor_gain	1.0000
4:78252519:G:GT	donor_gain	1.0000
4:78252548:GGGA:G	donor_gain	1.0000
4:78252549:GGA:G	donor_gain	1.0000
4:78252549:GGAG:G	donor_gain	1.0000
4:78252550:GAG:G	donor_gain	1.0000
4:78252552:G:GG	donor_gain	1.0000
4:78257562:A:G	acceptor_gain	1.0000
4:78265009:T:A	acceptor_gain	1.0000
4:78286387:A:AG	acceptor_gain	1.0000
4:78286388:A:G	acceptor_gain	1.0000
4:78286390:A:AG	acceptor_gain	1.0000
4:78286391:T:G	acceptor_gain	1.0000
4:78286396:T:TA	acceptor_gain	1.0000
4:78308064:A:AG	acceptor_gain	1.0000
4:78308065:G:GG	acceptor_gain	1.0000
4:78315592:A:AG	acceptor_gain	1.0000
4:78315593:G:GG	acceptor_gain	1.0000
4:78315593:GC:G	acceptor_gain	1.0000
4:78315593:GCTT:G	acceptor_gain	1.0000
4:78318808:A:AG	acceptor_gain	1.0000
4:78318809:G:GG	acceptor_gain	1.0000
4:78318809:GCCT:G	acceptor_gain	1.0000
4:78333270:A:AG	acceptor_gain	1.0000
4:78333271:G:GG	acceptor_gain	1.0000
4:78333271:GCTT:G	acceptor_gain	1.0000
4:78333398:A:T	donor_gain	1.0000

AlphaMissense

26572 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001955 (4:78082336 A>G), RS1000019023 (4:78509920 C>T), RS1000022613 (4:78419752 G>A,T), RS10000275 (4:78399161 G>A), RS1000028714 (4:78220695 A>C), RS1000029725 (4:78263932 A>G), RS1000045969 (4:78196243 G>C), RS1000046967 (4:78125601 C>G), RS1000049654 (4:78191826 A>G), RS1000055399 (4:78321633 C>T), RS1000055602 (4:78074061 G>A), RS1000064107 (4:78386956 A>G), RS10000651 (4:78158915 G>A), RS1000074987 (4:78271197 T>C,G), RS1000077638 (4:78407117 A>G)

Disease associations

OMIM: gene MIM:607830 | disease phenotypes: MIM:219000, MIM:191830, MIM:610805, MIM:142340, MIM:605472, MIM:119530

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Fraser syndrome	Definitive	AR

Mondo (11): Fraser syndrome 1 (MONDO:0054737), renal agenesis (MONDO:0018470), congenital anomaly of kidney and urinary tract (MONDO:0019719), myoepithelial tumor (MONDO:0002380), congenital diaphragmatic hernia (MONDO:0005711), Usher syndrome type 2C (MONDO:0011558), Rieger anomaly (MONDO:0019628), Fraser syndrome (MONDO:0009046), microcephaly (MONDO:0001149), orofacial cleft 1 (MONDO:0007335), renal agenesis, unilateral (MONDO:0019636)

Orphanet (8): Fraser syndrome (Orphanet:2052), Renal agenesis (Orphanet:411709), Renal or urinary tract malformation (Orphanet:93545), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Congenital diaphragmatic hernia (Orphanet:2140), Usher syndrome type 2 (Orphanet:231178), Usher syndrome (Orphanet:886), Rieger anomaly (Orphanet:91483)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000079	Abnormality of the urinary system
HP:0000089	Renal hypoplasia
HP:0000142	Abnormal vagina morphology
HP:0000148	Vaginal atresia
HP:0000175	Cleft palate
HP:0000183	Tongue muscle weakness
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
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:0000378	Cupped ear
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000519_9	Hair morphology	7.000000e-08
GCST001801_3	Uric acid levels	6.000000e-06
GCST003440_2	Response to carboplatin in ovarian cancer (MTT IC50)	6.000000e-07
GCST003542_16	Night sleep phenotypes	3.000000e-06
GCST004722_2	Left ventricular obstructive tract defect (maternal effect)	2.000000e-06
GCST004862_47	Itch intensity from mosquito bite adjusted by bite size	6.000000e-06
GCST005171_38	QT interval	2.000000e-06
GCST005191_6	Hair shape	1.000000e-12
GCST006988_15	Blond vs. brown/black hair color	2.000000e-21
GCST007431_42	Lung function (FEV1/FVC)	2.000000e-16
GCST009959_23	Retinal detachment or retinal break	4.000000e-06
GCST012490_181	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST012490_277	Femur bone mineral density x serum urate levels interaction	3.000000e-09
GCST90002384_138	Hemoglobin	7.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005038	hair morphology
EFO:0004761	uric acid measurement
EFO:0006952	cytotoxicity measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004682	QT interval
EFO:0003924	hair color
EFO:0004713	FEV/FVC ratio
EFO:0010698	retinal break
EFO:0004531	urate measurement
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (7)

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
D009208	Myoepithelioma	C04.557.435.585
C566906	Cakut (supp.)
C566121	Orofacial Cleft 1 (supp.)
C536492	Usher syndrome, type 2C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4386623	FRAS1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	6
Valproic Acid	affects expression, affects cotreatment, increases expression	5
sodium arsenite	affects methylation, decreases expression, increases expression	4
Cisplatin	affects expression, affects cotreatment, decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
deoxynivalenol	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
butyraldehyde	decreases expression	1
tobacco tar	increases expression	1
ochratoxin A	decreases expression	1
nivalenol	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

113 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
NCT00257946	PHASE3	TERMINATED	Type of Material in Repair of Congenital Diaphragmatic Hernia
NCT03861182	PHASE3	TERMINATED	Contribution of PRF in CDH in Children With Prothetic Patch Closure
NCT06946576	PHASE3	NOT_YET_RECRUITING	Safety and Efficacy of Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT00373438	PHASE2	UNKNOWN	Fetoscopic Tracheal Balloon Occlusion in Left Diaphragmatic Hernia
NCT00966823	PHASE2	TERMINATED	Fetal Tracheal Balloon Study in Diaphragmatic Hernia
NCT01302977	PHASE2	UNKNOWN	Fetal Tracheal Occlusion in Severe Diaphragmatic Hernia: a Randomized Trial
NCT01731509	PHASE2	UNKNOWN	Early FETO for Severe Congenital Diaphragmatic Hernia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT05201144	PHASE2	RECRUITING	A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT03526588	PHASE1	TERMINATED	Umbilical Cord Blood Mononuclear Cells for Hypoxic Neurologic Injury in Infants With Congenital Diaphragmatic Hernia (CDH)
NCT00032877	Not specified	COMPLETED	Genetic Analysis of Fraser Syndrome and Fryns Syndrome
NCT01831141	Not specified	UNKNOWN	Long Term Outcome of Congenital Solitary Kidney
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT00371241	Not specified	COMPLETED	Antibody Secreting Cell and Cyotokine Profiles in Neonates on ECMO
NCT00373763	Not specified	WITHDRAWN	Fetoscopic Tracheal Balloon Occlusion in Unborns With Severe Congenital Diaphragmatic Hernia - EUROTRIAL I
NCT00763737	Not specified	COMPLETED	Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
NCT00881660	Not specified	COMPLETED	Fetal Endotracheal Occlusion (FETO) in Severe and Extremely Severe Congenital Diaphragmatic Hernia
NCT00950118	Not specified	RECRUITING	Diaphragmatic Hernia Research & Exploration, Advancing Molecular Science
NCT01098929	Not specified	UNKNOWN	Gene Mutations and Rescue in Human Congenital Diaphragmatic Hernia
NCT01155830	Not specified	COMPLETED	Inflammatory Cytokine Quantification in Infants
NCT01243229	Not specified	COMPLETED	Genetic Analysis of Congenital Diaphragmatic Disorders
NCT01467245	Not specified	COMPLETED	Open or Keyhole Surgery Through the Chest for Newborn Babies: Effect on Blood Gases
NCT01921309	Not specified	UNKNOWN	Trinity™ BIOLOX Delta™ CoC THR Multi-center Study
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT02453750	Not specified	COMPLETED	Airway Inflammation in Congenital Diaphragmatic Hernia Patients
NCT02466451	Not specified	COMPLETED	Study in Children With the Diagnosis of Congenital Diaphragmatic Hernia (CDH) and Oesophageal Atresia (EA)