Fraser syndrome 1

Summary

Fraser syndrome 1 (MONDO:0054737) is a disease caused by variants in FRAS1 and FREM2, with 4 cohort genes.

At a glance

• Causal genes: FRAS1 (GenCC Definitive), FREM2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 1,209

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fraser syndrome 1
Mondo ID	MONDO:0054737
OMIM	219000
DOID	DOID:0111405
UMLS	C4551480
MedGen	1639061
GARD	0025962
Is cancer (heuristic)	no

Also known as: Fraser syndrome 1 · FRASRS1

Data availability: 1,209 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Fraser syndrome › Fraser syndrome 1

Related subtypes (2): Fraser syndrome 2, Fraser syndrome 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

256 uncertain significance, 109 benign, 108 conflicting classifications of pathogenicity, 37 benign/likely benign, 31 likely pathogenic, 25 pathogenic/likely pathogenic, 23 pathogenic, 11 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027394	NM_025074.7(FRAS1):c.4259G>A (p.Trp1420Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027395	NM_025074.7(FRAS1):c.6433C>T (p.Arg2145Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065638	NM_025074.7(FRAS1):c.6202A>T (p.Lys2068Ter)	FRAS1	Pathogenic	criteria provided, single submitter
1074280	NM_025074.7(FRAS1):c.6805C>T (p.Arg2269Ter)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179032	NM_025074.7(FRAS1):c.7254dup (p.Glu2419fs)	FRAS1	Pathogenic	criteria provided, single submitter
1179131	NM_025074.7(FRAS1):c.364del (p.Glu122fs)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1302906	NM_025074.7(FRAS1):c.10261C>T (p.Arg3421Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322936	NM_025074.7(FRAS1):c.2692del (p.His898fs)	FRAS1	Pathogenic	criteria provided, single submitter
1332873	NM_025074.7(FRAS1):c.3293-2A>T	FRAS1	Pathogenic	criteria provided, single submitter
1341530	NM_025074.7(FRAS1):c.5166del (p.Val1723fs)	FRAS1	Pathogenic	criteria provided, single submitter
1343039	NM_025074.7(FRAS1):c.934C>T (p.Gln312Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705727	NM_025074.7(FRAS1):c.2376del (p.Ser793fs)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
194789	NM_025074.7(FRAS1):c.1931del (p.Gly644fs)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195697	NM_025074.7(FRAS1):c.2722+1G>A	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197861	NM_025074.7(FRAS1):c.370C>T (p.Arg124Ter)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2024612	NM_025074.7(FRAS1):c.9575del (p.Pro3192fs)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219182	NM_025074.7(FRAS1):c.10287del (p.Leu3428_Tyr3429insTer)	FRAS1	Pathogenic	no assertion criteria provided
219183	NM_025074.7(FRAS1):c.5664_5665+19delinsT	FRAS1	Pathogenic	no assertion criteria provided
235484	NM_025074.7(FRAS1):c.7551T>A (p.Tyr2517Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441786	NM_025074.7(FRAS1):c.8922del (p.Asp2975fs)	FRAS1	Pathogenic	criteria provided, single submitter
2501255	NM_025074.7(FRAS1):c.13A>T (p.Lys5Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2724035	NM_025074.7(FRAS1):c.5927_5928del (p.Ile1976fs)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2746739	NM_025074.7(FRAS1):c.562C>T (p.Gln188Ter)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2755916	NM_025074.7(FRAS1):c.9181dup (p.Ala3061fs)	FRAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2785145	NM_025074.7(FRAS1):c.748_758del (p.Arg250fs)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2790381	NM_025074.7(FRAS1):c.11110C>T (p.Arg3704Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2809	NM_025074.7(FRAS1):c.8602C>T (p.Gln2868Ter)	FRAS1	Pathogenic	criteria provided, single submitter
2810	NM_025074.7(FRAS1):c.9013C>T (p.Gln3005Ter)	FRAS1	Pathogenic	no assertion criteria provided
2812	NM_025074.7(FRAS1):c.3799C>T (p.Gln1267Ter)	FRAS1	Pathogenic	no assertion criteria provided
2813	NM_025074.7(FRAS1):c.4271C>G (p.Ser1424Ter)	FRAS1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FRAS1	Definitive	Autosomal recessive	Fraser syndrome 1	5
FREM2	Definitive	Autosomal recessive	Fraser syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FRAS1	Orphanet:2052	Fraser syndrome
FRAS1	Orphanet:93100	Renal agenesis, unilateral
FREM2	Orphanet:2052	Fraser syndrome
FREM2	Orphanet:93100	Renal agenesis, unilateral
FREM2	Orphanet:98949	Complete cryptophthalmia
GRIP1	Orphanet:2052	Fraser syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FRAS1	HGNC:19185	ENSG00000138759	Q86XX4	Extracellular matrix organizing protein FRAS1	gencc,clinvar
FREM2	HGNC:25396	ENSG00000150893	Q5SZK8	FRAS1-related extracellular matrix protein 2	gencc,clinvar
GRIP1	HGNC:18708	ENSG00000155974	Q9Y3R0	Glutamate receptor-interacting protein 1	clinvar
NCOA2	HGNC:7669	ENSG00000140396	Q15596	Nuclear receptor coactivator 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FRAS1	Extracellular matrix organizing protein FRAS1	Involved in extracellular matrix organization.
FREM2	FRAS1-related extracellular matrix protein 2	Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia.
GRIP1	Glutamate receptor-interacting protein 1	May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons.
NCOA2	Nuclear receptor coactivator 2	Transcriptional coactivator for steroid receptors and nuclear receptors.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	4.3×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FRAS1	Other/Unknown	no		EGF, VWF_dom, Calx_beta
FREM2	Other/Unknown	no		Calx_beta, CalX-like_sf, CSPG_rpt
GRIP1	Scaffold/PPI	no		PDZ, PDZ_sf, PDZ_6
NCOA2	Transcription factor	no		PAS, Nuc_rcpt_coact, NCO_DUF1518

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
renal medulla	2
germinal epithelium of ovary	1
parietal pleura	1
adrenal tissue	1
kidney epithelium	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
corpus epididymis	1
endothelial cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FRAS1	212	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, renal medulla
FREM2	160	broad	marker	adrenal tissue, kidney epithelium, renal medulla
GRIP1	192	broad	marker	cortical plate, ganglionic eminence, ventricular zone
NCOA2	292	ubiquitous	marker	corpus epididymis, endothelial cell, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIP1	3,602
FRAS1	2,552
NCOA2	2,464
FREM2	1,652

Intra-cohort edges

A	B	Sources
FRAS1	FREM2	string_interaction
FRAS1	GRIP1	string_interaction
FREM2	GRIP1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCOA2	Q15596	381
GRIP1	Q9Y3R0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FRAS1	Q86XX4
FREM2	Q5SZK8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	380.7×	0.025	NCOA2
R-HSA-1368082	1	356.9×	0.025	NCOA2
Cytochrome P450 - arranged by substrate type	1	356.9×	0.025	NCOA2
Trafficking of GluR2-containing AMPA receptors	1	335.9×	0.025	GRIP1
Recycling of bile acids and salts	1	300.5×	0.025	NCOA2
Bile acid and bile salt metabolism	1	248.3×	0.025	NCOA2
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	228.4×	0.025	NCOA2
BMAL1:CLOCK,NPAS2 activates circadian expression	1	211.5×	0.025	NCOA2
Synthesis of bile acids and bile salts	1	203.9×	0.025	NCOA2
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	203.9×	0.025	NCOA2
Endogenous sterols	1	196.9×	0.025	NCOA2
R-HSA-400253	1	173.0×	0.025	NCOA2
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.025	NCOA2
RHO GTPases activate PKNs	1	158.6×	0.025	NCOA2
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.025	NCOA2
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.025	NCOA2
SUMOylation of transcription cofactors	1	121.5×	0.025	NCOA2
Phase I - Functionalization of compounds	1	109.8×	0.025	NCOA2
Heme signaling	1	107.7×	0.025	NCOA2
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.025	NCOA2
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.025	NCOA2
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.025	NCOA2
Cytoprotection by HMOX1	1	92.1×	0.025	NCOA2
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.025	NCOA2
Mitochondrial biogenesis	1	84.0×	0.025	NCOA2
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	1	84.0×	0.025	NCOA2
SUMOylation	1	81.6×	0.025	NCOA2
Adipogenesis	1	78.2×	0.025	NCOA2
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.025	NCOA2
Cellular response to chemical stress	1	71.4×	0.025	NCOA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell communication	2	421.3×	3e-04	FRAS1, FREM2
morphogenesis of an epithelium	2	172.0×	8e-04	FRAS1, FREM2
anatomical structure morphogenesis	2	69.6×	0.003	FRAS1, FREM2
metanephros morphogenesis	1	1053.2×	0.006	FRAS1
cellular response to Thyroglobulin triiodothyronine	1	1053.2×	0.006	NCOA2
positive regulation of neuron projection arborization	1	526.6×	0.009	GRIP1
neurotransmitter receptor transport, endosome to postsynaptic membrane	1	468.1×	0.009	GRIP1
peroxisome proliferator activated receptor signaling pathway	1	383.0×	0.009	NCOA2
regulation of cellular response to insulin stimulus	1	383.0×	0.009	NCOA2
locomotor rhythm	1	263.3×	0.011	NCOA2
positive regulation of adipose tissue development	1	263.3×	0.011	NCOA2
regulation of glucose metabolic process	1	140.4×	0.018	NCOA2
response to progesterone	1	123.9×	0.018	NCOA2
negative regulation of smoothened signaling pathway	1	113.9×	0.018	NCOA2
skin development	1	110.9×	0.018	FRAS1
regulation of lipid metabolic process	1	108.0×	0.018	NCOA2
embryonic limb morphogenesis	1	100.3×	0.018	FRAS1
cellular response to hormone stimulus	1	95.8×	0.018	NCOA2
inner ear development	1	93.6×	0.018	FREM2
eye development	1	87.8×	0.018	FREM2
mRNA transcription by RNA polymerase II	1	82.6×	0.018	NCOA2
embryonic digit morphogenesis	1	75.2×	0.019	FREM2
roof of mouth development	1	62.0×	0.022	FRAS1
circadian regulation of gene expression	1	58.5×	0.023	NCOA2
kidney development	1	35.1×	0.036	FREM2
heart development	1	19.7×	0.061	FREM2
protein transport	1	11.0×	0.104	FRAS1
intracellular signal transduction	1	9.5×	0.113	GRIP1
cell adhesion	1	9.4×	0.113	FREM2
regulation of DNA-templated transcription	1	7.9×	0.129	NCOA2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NCOA2	METHYLENE BLUE ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NCOA2	1	4
FRAS1	0	0
FREM2	0	0
GRIP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
METHYLENE BLUE ANHYDROUS	4	NCOA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NCOA2	3	Functional:2, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
METHYLENE BLUE ANHYDROUS	4	NCOA2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NCOA2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FRAS1, FREM2, GRIP1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FRAS1	0	—
FREM2	0	—
GRIP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.