FGF12

Chr 3AD

fibroblast growth factor 12

Also known as: DEE47, EIEE47, FGF12B, FHF1

NCBI Gene: 2257 ENSG00000114279 UniProt: P61328 OMIM: 601513

The protein is a member of the fibroblast growth factor family that lacks a signal sequence and instead localizes to the nucleus rather than being secreted. Mutations cause developmental and epileptic encephalopathy 47 through an autosomal dominant inheritance pattern. The specific mechanism by which nuclear FGF12 dysfunction leads to seizures and developmental delay remains unclear.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth, and invasion. This growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.541 OMIM phenotype

Clinical Summary— FGF12

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Gene-Disease Validity (ClinGen)

Brugada syndrome · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 104 VUS of 282 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FGF12

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.623

Z-score 2.63

OE 0.17 (0.07–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.52Z-score

OE missense 0.64 (0.54–0.76)

91 obs / 142.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.54)

0≤0.351.4

Missense OE?0.64 (0.54–0.76)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 2 / 11.7Missense obs/exp: 91 / 142.1Syn Z: 0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFGF12-related epileptic encephalopathyGOFAD

This gene — mechanism propensity

0.5180th %ile

GOF

0.6442th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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 · 1 literature citation

LOF17% of P/LP variants are LoF

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.

Literature Evidence

GOFGain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27164707 ↗

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic5

VUS104

Likely Benign105

Benign55

Conflicting5

Pathogenic

Likely Pathogenic

104

VUS

105

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	3	1	0	5
VUS	6	84	13	1	104
Likely Benign	0	16	47	42	105
Benign	0	11	41	3	55
Conflicting	—				5
Total	7	115	102	46	275

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap FGF12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →