FAT2

Chr 5AD

FAT atypical cadherin 2

Also known as: CDHF8, CDHR9, HFAT2, MEGF1, SCA45

NCBI Gene: 2196 ENSG00000086570 UniProt: Q9NYQ8 OMIM: 604269

This protein functions as a cell adhesion molecule that regulates cell migration and mediates organization of parallel fibers during cerebellar development. Mutations cause spinocerebellar ataxia 45, a movement disorder primarily affecting the cerebellum, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, indicating it is intolerant to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is the second identified human homolog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has two epidermal growth factor (EGF)-like repeats and one laminin G domain. This protein most likely functions as a cell adhesion molecule, controlling cell proliferation and playing an important role in cerebellum development. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.511 OMIM phenotype

Clinical Summary— FAT2

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 6.38

OE 0.40 (0.32–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.72Z-score

OE missense 0.96 (0.93–0.99)

2292 obs / 2390.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.32–0.51)

0≤0.351.4

Missense OE?0.96 (0.93–0.99)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 54 / 133.6Missense obs/exp: 2292 / 2390.6Syn Z: -1.00

This gene — mechanism propensity

0.7035th %ile

GOF

0.6638th %ile

LOF

0.3454th %ile

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

DNprediction above median

GOFprediction 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.