FRS2

protein-coding

fibroblast growth factor receptor substrate 2

Gene summary

Enables fibroblast growth factor receptor binding activity and neurotrophin TRKA receptor binding activity. Involved in negative regulation of cardiac muscle cell differentiation. Acts upstream of or within fibroblast growth factor receptor signaling pathway. Located in adherens junction. Biomarker of renal cell carcinoma. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001278356.2

Inheritance

—

ClinVar variants

U:65B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr12:69,470,349-69,579,793

External References & Databases

Ensembl (ENSG00000166225)

Transcript & Mutation Effects

hg38 • Region Span ~109.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FRS2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 63

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278356.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar			1
missense			62 clinvar	1 clinvar		63
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	65	1	0	66

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278356.2	RefSeq	NP_001265285.1	5	MANE Select
ENST00000549921.6	Ensembl	ENSP00000450048.1	5	MANE Select
NM_001042555.3	RefSeq	NP_001036020.1	5	Standard
NM_001278351.2	RefSeq	NP_001265280.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)
Angiogenesis overview
Brain-Derived Neurotrophic Factor (BDNF) signaling pathway

Biological Process

MAPK cascade
activation of MAPKK activity
activation of MAPK activity
gastrulation with mouth forming second
organ induction

Molecular Function

transmembrane receptor protein tyrosine kinase adaptor activity
Ras guanyl-nucleotide exchange factor activity
fibroblast growth factor receptor binding
neurotrophin TRKA receptor binding
protein binding

Cellular Component

cytosol
plasma membrane
integral component of plasma membrane
cell-cell adherens junction
endomembrane system

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299293
Coding exons: 5
Length: 109434
Individuals with no LoFs: 124776
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 124781
p: 0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	236	290	0.813	0.0000157	3330
Missense (PolyPhen)		50	86.309	0.57931		911
Synonymous	0.798	91	101	0.899	0.00000487	1010
Loss of Function	4.12	1	21.7	0.0461	0.00000142	242

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1. {ECO:0000269|PubMed:12974390, ECO:0000269|PubMed:21765395}.;

Intolerance Scores

LoFtool: 0.180
RVIS EVS: -0.27
RVIS percentile EVS: 34.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.677

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium