FAT1

Chr 4

FAT atypical cadherin 1

Also known as: CDHF7, CDHR8, FAT, ME5, hFat1

NCBI Gene: 2195 ENSG00000083857 UniProt: Q14517 OMIM: 600976

FAT1 encodes a large cadherin superfamily protein that functions as an adhesion molecule and signaling receptor essential for cellular polarization, directed cell migration, and modulating cell-cell contact. Mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) with autosomal dominant inheritance, affecting facial, shoulder, and upper arm muscles. The gene is highly constrained against loss-of-function variants, indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene is an ortholog 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 five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.43

Clinical Summary— FAT1

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Gene-Disease Validity (ClinGen)

focal segmental glomerulosclerosis · ARStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.000

Z-score 7.35

OE 0.34 (0.27–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.43Z-score

OE missense 1.02 (0.99–1.06)

2611 obs / 2549.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.34 (0.27–0.43)

0≤0.351.4

Missense OE?1.02 (0.99–1.06)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 49 / 144.2Missense obs/exp: 2611 / 2549.8Syn Z: -2.04

This gene — mechanism propensity

0.6936th %ile

GOF

0.6053th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.