FRMD4A

Chr 10

FERM domain containing 4A

Also known as: CCAFCA, FRMD4, bA295P9.4

NCBI Gene: 55691ENSG00000151474UniProt: Q9P2Q2

This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer's disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

UniProtAgenesis of the corpus callosum, with facial anomalies and cerebellar ataxia
261
ClinVar variants
22
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FRMD4A
⚡
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
22 Pathogenic / Likely Pathogenic· 187 VUS of 261 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.14LOEUF
pLI 1.000
Z-score 6.64
OE 0.05 (0.02–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
2.46Z-score
OE missense 0.72 (0.67–0.78)
447 obs / 618.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.05 (0.02–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.78)
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.1.07
0≤1.21.6
LoF obs/exp: 3 / 57.2Missense obs/exp: 447 / 618.9Syn Z: -0.85

ClinVar Variant Classifications

261 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic3
VUS187
Likely Benign35
Benign17
19
Pathogenic
3
Likely Pathogenic
187
VUS
35
Likely Benign
17
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
18
0
19
Likely Pathogenic
1
1
1
0
3
VUS
1
174
12
0
187
Likely Benign
0
2
9
24
35
Benign
0
2
10
5
17
Total31795029261

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

View in ClinVar →

Protein Context — Lollipop Plot

FRMD4A · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genomic and phenotypic delineation of congenital microcephaly.
Shaheen R et al.·Genet Med
2019
Integration of scRNA-Seq and scATAC-Seq Reveals Malignant Characteristics of Sarcomatoid Clear Cell Renal Cell Carcinoma.
Lu W et al.·Cancer Sci
2025
FRMD4A: A potential therapeutic target for the treatment of tongue squamous cell carcinoma.
Zheng X et al.·Int J Mol Med
2016
Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.
Stoltze UK et al.·J Med Genet
2023Cohort
Association of genetic risk factors with cognitive decline: the PATH through life project.
Andrews SJ et al.·Neurobiol Aging
2016
Down regulation of Cathepsin W is associated with poor prognosis in pancreatic cancer.
Khojasteh-Leylakoohi F et al.·Sci Rep
2023
Pathogenic Factors Identification of Brain Imaging and Gene in Late Mild Cognitive Impairment.
Bi XA et al.·Interdiscip Sci
2021
FRMD4A/RET: A Novel RET Oncogenic Fusion Variant in Non-Small Cell Lung Carcinoma.
Velcheti V et al.·J Thorac Oncol
2017Case report
Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation.
Breton CV et al.·PLoS One
2014
Identification of Functional Genetic Variants Associated With Alcohol Dependence and Related Phenotypes Using a High-Throughput Assay.
Thapa KS et al.·Alcohol Clin Exp Res
2020Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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