FAS - dismech genes

Normal function · from ai-gene-review (P25445, commit 79fe13b38970) · AI-generated, not KB evidence

FAS (CD95/APO-1) is a death receptor that triggers extrinsic apoptosis. CRITICAL ISOFORM BIOLOGY: Alternative splicing produces 7 isoforms with ANTAGONISTIC functions: (1) Membrane-bound isoform 1 (P25445-1) forms the DISC with FADD and CASP8 to trigger apoptosis; (2) Soluble isoforms 2-6 (lacking transmembrane domain) act as DECOY RECEPTORS that BLOCK apoptosis by binding FasL without signaling. UniProt states "The secreted isoforms 2 to 6 block apoptosis (in vitro)". The GOA has BOTH GO:0043065 (positive regulation) AND GO:0043066 (negative regulation) of apoptosis - this reflects isoform conflation where membrane and soluble forms have opposite effects. LIGAND-FORM CHECKPOINT: membrane-bound FasL (mFASL) drives canonical apoptotic DISC signaling, while soluble FasL (sFASL) preferentially biases toward NON-APOPTOTIC programs (NF-kB, MAPK, PI3K/AKT) via alternative membrane-associated complexes (FADDosome/MISC), supporting inflammation, migration, and proliferation (Hu 2025 PMID:40330016; Seyrek et al. 2024 PMID:39513921). HUMAN GENETICS: heterozygous FAS variants cause autoimmune lymphoproliferative syndrome (ALPS); a 2024 cohort of 802 referred patients found pathogenic/likely-pathogenic FAS variants in 6.5% of the total cohort, with 58% located in the intracellular domain and 57% of those being missense changes in the death domain - underscoring the death domain as the critical functional module for in vivo apoptotic signaling (Xu et al. 2024 PMID:39060684).

FAS (CD95/APO-1) is a type I transmembrane death receptor of the TNF receptor superfamily (TNFRSF6). The extracellular domain contains three cysteine-rich domains (CRDs) that bind FasL (FASLG/CD95L). This is the defining molecular function of FAS. ISOFORM-SPECIFIC to membrane-bound isoform 1 (P25445-1).

molecular function: tumor necrosis factor receptor activity · directly involved in: extrinsic apoptotic signaling pathway via death domain receptors; Fas signaling pathway · locations: external side of plasma membrane; membrane raft · in complex: CD95 death-inducing signaling complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Autoimmune Lymphoproliferative Syndrome	causative	mechanism: Defective Fas-Mediated Lymphocyte Apoptosis subtype: ALPS-FAS; ALPS-sFAS scoped to subtype: ALPS-FAS
Evans Syndrome	causative germline	mechanism: Loss of Lymphocyte Self-Tolerance
Rosai-Dorfman Disease	susceptibility germline
FAS-related Autoimmune Lymphoproliferative Syndrome	untyped CAUSATIVE	mechanism: Defective Fas-mediated apoptosis of activated lymphocytes
Multisystem Inflammatory Syndrome in Children (MIS-C)	untyped Implicated in immune dysregulation	mechanism: T-Cell Receptor Vβ21.3 Skewing and IL-18-FAS Activation
Stevens-Johnson Syndrome	no genetic record	mechanism: Fas-FasL Keratinocyte Apoptosis
Systemic Lupus Erythematosus	no genetic record	animal model: MRL/lpr

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
FAS-related autoimmune lymphoproliferative immune disorder MONDO:1060194	SD	Definitive 2025-10-14	Autoimmune Lymphoproliferative Syndrome causative FAS-related Autoimmune Lymphoproliferative Syndrome untyped