FAT4

Chr 4AR

FAT atypical cadherin 4

Also known as: CDHF14, CDHR11, FAT-J, FATJ, HKLLS2, NBLA00548, VMLDS2

NCBI Gene: 79633ENSG00000196159UniProt: Q6V0I7

The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

Hennekam lymphangiectasia-lymphedema syndrome 2MIM #616006
AR
Van Maldergem syndrome 2MIM #615546
AR
566
ClinVar variants
18
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FAT4
🧬
Gene-Disease Validity (ClinGen)
FAT4-related neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 274 VUS of 566 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.18LOEUF
pLI 1.000
Z-score 9.37
OE 0.12 (0.08–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.62Z-score
OE missense 0.97 (0.93–1.00)
2545 obs / 2634.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.08–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.93–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 16 / 132.3Missense obs/exp: 2545 / 2634.8Syn Z: -1.30

ClinVar Variant Classifications

566 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic4
VUS274
Likely Benign270
Benign4
14
Pathogenic
4
Likely Pathogenic
274
VUS
270
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
0
4
0
14
Likely Pathogenic
2
0
2
0
4
VUS
0
269
5
0
274
Likely Benign
0
4
30
236
270
Benign
0
1
2
1
4
Total1227443237566

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

View in ClinVar →

Protein Context — Lollipop Plot

FAT4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FAT4-related Hennekam lymphangiectasia-lymphedema syndrome

definitive
ARUndeterminedUncertain
Dev. Disorders
G2P ↗

FAT4-related Van Maldergem syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hennekam lymphangiectasia-lymphedema syndrome 2

MIM #616006

Molecular basis of disorder known

Autosomal recessive

Van Maldergem syndrome 2

MIM #615546

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FAT4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
IL-32 aggravates metabolic disturbance in human nucleus pulposus cells by activating FAT4-mediated Hippo/YAP signaling.
Li P et al.·Int Immunopharmacol
2024
Dchs1-Fat4 regulation of osteogenic differentiation in mouse.
Crespo-Enriquez I et al.·Development
2019Functional
A pan-cancer analysis of FAT atypical cadherin 4 (FAT4) in human tumors.
Mao W et al.·Front Public Health
2022
Gastric cancer-molecular and clinical dimensions.
Wadhwa R et al.·Nat Rev Clin Oncol
2013Review
FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer.
Malgundkar SH et al.·BMC Cancer
2020
Dissecting the tumor microenvironment in primary breast angiosarcoma: insights from single-cell RNA sequencing.
Ding P et al.·Breast Cancer Res
2025
Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma.
Villa M et al.·Br J Cancer
2024
Hepatoid adenocarcinoma of the stomach and non-hepatoid alpha-fetoprotein-producing gastric cancer exhibit a high degree of molecular similarity.
Chen L et al.·Cell Oncol (Dordr)
2025
Identification of FAT4 as a positive prognostic biomarker in DLBCL by comprehensive genomic analysis.
Lv L et al.·Clin Exp Med
2023
Age-related mutations and chronic myelomonocytic leukemia.
Mason CC et al.·Leukemia
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RETRACTION: miR-107 Regulates Growth and Metastasis of Gastric Cancer Cells via Activation of the PI3K-AKT Signaling Pathway by Down-Regulating FAT4.
·Cancer Med
2026
Establishment and Evaluation of Prognostic Prediction Model for Diffuse Large B-Cell Lymphoma Patients Based on International Prognostic Index and FAT4, TP53 Mutation.
Shao L et al.·Acta Haematol
2025Cohort
UBE4B promotes gastric cancer proliferation and metastasis by mediating FAT4 ubiquitination and degradation.
Wu K et al.·Cell Death Dis
2025🔓 Open Access
Fat4 intracellular domain controls internalization of Fat4/Dchs1 planar polarity membrane complexes.
Easa Y et al.·Biophys J
2025
LATS2 and FAT4 as key candidate genes of hippo pathway associated with the risk and progression of breast cancer: an in-silico approach.
Sadaf et al.·Sci Rep
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools