CFLAR

Chr 2

CASP8 and FADD like apoptosis regulator

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

NCBI Gene: 8837 ENSG00000003402 UniProt: O15519

The protein encoded by CFLAR regulates apoptosis by inhibiting TNFRSF6-mediated cell death and blocking caspase-8 processing in the death-inducing signaling complex. Mutations cause autosomal recessive immunodeficiency with recurrent infections, lymphoproliferation, and autoimmunity. The gene is highly constrained against loss-of-function variants, indicating that biallelic mutations are required for disease.

ResearchSummary from RefSeq, UniProt

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]

ResearchGenerating clinical summary…

LOEUF 0.17

Clinical Summary— CFLAR

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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.

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ClinVar Variants

32 VUS of 52 total submissions

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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?

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?

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?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.61 (0.54–0.70)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 1 / 27.4Missense obs/exp: 154 / 251.6Syn Z: 1.03

ClinVar Variant Classifications

52 submitted variants in ClinVar

ClinVar

Classification Summary

VUS32

Likely Benign3

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	32	0	32
Likely Benign	3	0	3
Benign	1	1	2
Total	36	1	37

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap CFLAR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →