Fraser syndrome 2

Summary

Fraser syndrome 2 (MONDO:0054738) is a disease caused by FREM2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: FREM2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 831

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fraser syndrome 2
Mondo ID	MONDO:0054738
OMIM	617666
DOID	DOID:0111407
UMLS	C4540036
MedGen	1624349
GARD	0025963
Is cancer (heuristic)	no

Also known as: Fraser syndrome 2 · FRASRS2

Data availability: 831 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Fraser syndrome › Fraser syndrome 2

Related subtypes (2): Fraser syndrome 1, 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:

409 uncertain significance, 69 conflicting classifications of pathogenicity, 64 benign, 19 benign/likely benign, 16 likely pathogenic, 13 likely benign, 6 pathogenic/likely pathogenic, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322940	NM_207361.6(FREM2):c.2833del (p.His945fs)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687536	NM_207361.6(FREM2):c.3151C>T (p.Gln1051Ter)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1986	NM_207361.6(FREM2):c.7519+1G>A	FREM2	Pathogenic	no assertion criteria provided
2104116	NM_207361.6(FREM2):c.7477_7478del (p.Leu2493fs)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2583092	NM_207361.6(FREM2):c.2689C>T (p.Gln897Ter)	FREM2	Pathogenic	no assertion criteria provided
2784732	NM_207361.6(FREM2):c.5982del (p.Ala1996fs)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2799204	NM_207361.6(FREM2):c.2425C>T (p.Arg809Ter)	FREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
285788	NM_207361.6(FREM2):c.5954dup (p.Met1985fs)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2865617	NM_207361.6(FREM2):c.3297dup (p.Asp1100Ter)	FREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
3012758	NM_207361.6(FREM2):c.3569del (p.Gln1190fs)	FREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252033	NM_207361.6(FREM2):c.2303C>G (p.Ser768Ter)	FREM2	Likely pathogenic	criteria provided, single submitter
1723213	NM_207361.6(FREM2):c.6680_6681dup (p.Phe2228fs)	FREM2	Likely pathogenic	no assertion criteria provided
2627892	NM_207361.6(FREM2):c.7546dup (p.Val2516fs)	FREM2	Likely pathogenic	criteria provided, single submitter
2630027	NM_207361.6(FREM2):c.2149C>T (p.Gln717Ter)	FREM2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664926	NM_207361.6(FREM2):c.8376del (p.Val2793fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3382229	NM_207361.6(FREM2):c.3737del (p.Thr1246fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3575967	NM_207361.6(FREM2):c.748del (p.Glu250fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3575968	NM_207361.6(FREM2):c.748G>T (p.Glu250Ter)	FREM2	Likely pathogenic	criteria provided, single submitter
3576028	NM_207361.6(FREM2):c.2646_2647del (p.Gln882fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3576036	NM_207361.6(FREM2):c.2876del (p.Asn959fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3576046	NM_207361.6(FREM2):c.3167G>A (p.Trp1056Ter)	FREM2	Likely pathogenic	criteria provided, single submitter
3576052	NM_207361.6(FREM2):c.3310_3311dup (p.Thr1105fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3576055	NM_207361.6(FREM2):c.3342T>G (p.Tyr1114Ter)	FREM2	Likely pathogenic	criteria provided, single submitter
3576084	NM_207361.6(FREM2):c.4232_4233del (p.Tyr1411fs)	FREM2	Likely pathogenic	criteria provided, single submitter
3576178	NM_207361.6(FREM2):c.6926-2A>T	FREM2	Likely pathogenic	criteria provided, single submitter
3576187	NM_207361.6(FREM2):c.7149del (p.Met2382_Tyr2383insTer)	FREM2	Likely pathogenic	criteria provided, single submitter
1179176	NM_207361.6(FREM2):c.8176+2dup	FREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1347477	NM_207361.6(FREM2):c.7366G>A (p.Asp2456Asn)	FREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1524852	NM_207361.6(FREM2):c.6201T>A (p.Asn2067Lys)	FREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1644095	NM_207361.6(FREM2):c.6578-7G>T	FREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
FREM2	Definitive	Autosomal recessive	Fraser syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FREM2	HGNC:25396	ENSG00000150893	Q5SZK8	FRAS1-related extracellular matrix protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FREM2	Other/Unknown	no		Calx_beta, CalX-like_sf, CSPG_rpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
kidney epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FREM2	160	broad	marker	adrenal tissue, kidney epithelium, renal medulla

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FREM2	1,652

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FREM2	Q5SZK8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	1	842.6×	0.006	FREM2
inner ear development	1	374.5×	0.006	FREM2
eye development	1	351.1×	0.006	FREM2
morphogenesis of an epithelium	1	343.9×	0.006	FREM2
embryonic digit morphogenesis	1	300.9×	0.006	FREM2
kidney development	1	140.4×	0.009	FREM2
anatomical structure morphogenesis	1	139.3×	0.009	FREM2
heart development	1	78.8×	0.014	FREM2
cell adhesion	1	37.5×	0.027	FREM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FREM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	FREM2

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.