FGFR4

Chr 5

fibroblast growth factor receptor 4

Also known as: CD334, JTK2, TKF

NCBI Gene: 2264ENSG00000160867UniProt: P22455OMIM: 134935

The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismLOEUF 0.871 OMIM phenotype
Clinical Summary— FGFR4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
100 VUS of 161 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — FGFR4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
0.87LOEUF
pLI 0.000
Z-score 2.24
OE 0.63 (0.46–0.87)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
1.19Z-score
OE missense 0.85 (0.79–0.92)
451 obs / 527.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.63 (0.46–0.87)
0≤0.351.4
Missense OE?0.85 (0.79–0.92)
0≤0.61.4
Synonymous OE?1.06
0≤1.21.6
LoF obs/exp: 26 / 41.5Missense obs/exp: 451 / 527.6Syn Z: -0.69

This gene — mechanism propensity

DN
0.80top 25%
GOF
0.83top 10%
LOF
0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

VUS100
Likely Benign16
Benign11
100
VUS
16
Likely Benign
11
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
0
0
0
0
VUS
2
97
0
1
100
Likely Benign
0
5
2
9
16
Benign
0
4
3
4
11
Total2106514127

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

62 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap FGFR4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

FGFR4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients