CFLAR

Chr 2

CASP8 and FADD like apoptosis regulator

Also known as: CASH, CASP8AP1, CLARP, Casper, FLAME, FLAME-1, FLAME1, FLIP

NCBI Gene: 8837ENSG00000003402UniProt: O15519

The protein encoded by this gene is a regulator of apoptosis and is structurally similar to caspase-8. However, the encoded protein lacks caspase activity and appears to be itself cleaved into two peptides by caspase-8. Several transcript variants encoding different isoforms have been found for this gene, and partial evidence for several more variants exists. [provided by RefSeq, Feb 2011]

74
ClinVar variants
32
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CFLAR
⚡
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
32 Pathogenic / Likely Pathogenic· 37 VUS of 74 total submissions

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.
0.17LOEUF
pLI 1.000
Z-score 4.67
OE 0.04 (0.01–0.17)
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.
2.19Z-score
OE missense 0.61 (0.54–0.70)
154 obs / 251.6 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.0.04 (0.01–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.54–0.70)
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.0.87
0≤1.21.6
LoF obs/exp: 1 / 27.4Missense obs/exp: 154 / 251.6Syn Z: 1.03

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic1
VUS37
Likely Benign3
Benign2
31
Pathogenic
1
Likely Pathogenic
37
VUS
3
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
31
0
31
Likely Pathogenic
0
0
1
0
1
VUS
0
32
5
0
37
Likely Benign
0
3
0
0
3
Benign
0
1
0
1
2
Total03637174

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

View in ClinVar →

Protein Context — Lollipop Plot

CFLAR · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
Pallavi R et al.·Nat Commun
2024
Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia.
Supper E et al.·Nat Commun
2021
Analyzing the molecular mechanism of Scutellaria Radix in the treatment of sepsis using RNA sequencing.
Deng Y et al.·BMC Infect Dis
2024Functional
MicroRNAs correlate with bacillary index and genes associated to cell death processes in leprosy.
de Lima Santana N et al.·Microbes Infect
2024
Deep learning and multi-omics reveal programmed cell death-associated diagnostic signatures and prognostic biomarkers in gastric cancer.
Jin Q et al.·Front Immunol
2025
Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia.
McLornan D et al.·Br J Haematol
2013
Genetic variants in cell death pathway genes and HBV-related hepatocellular carcinoma among a Chinese Han population.
Liu F et al.·Apoptosis
2017
Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL.
Moser R et al.·Cancer Res
2022
Exploring and validating the necroptotic gene regulation and related lncRNA mechanisms in colon adenocarcinoma based on multi-dimensional data.
Wang W et al.·Sci Rep
2024Functional
A Four-Gene Autophagy-Related Prognostic Model Signature and Its Association With Immune Phenotype in Lung Squamous Cell Carcinoma.
Luo L et al.·Cancer Rep (Hoboken)
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Nuclear respiratory factor-1 promotes CFLAR transcription in H9C2 cardiomyocytes, protecting them against hypoxia-induced apoptosis.
Li H et al.·Mol Biol Rep
2025
Potential role of CFLAR in enhancing 5-FU sensitivity and modulating immune cell infiltration in breast cancer.
Sun Y et al.·Eur J Med Res
2025🔓 Open Access
Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation.
Zhang H et al.·J Inflamm Res
2025🔓 Open AccessFunctional
Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing of Cflar in Ischemic Stroke With Hyperlipidemia.
Li R et al.·CNS Neurosci Ther
2024🔓 Open Access
The Regulatory Impact of CFLAR Methylation Modification on Liver Lipid Metabolism.
Ye C et al.·Int J Mol Sci
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