FAS

Chr 10AD

Fas cell surface death receptor

Also known as: ALPS1A, APO-1, APT1, CD95, FAS1, FASTM, TNFRSF6

NCBI Gene: 355 ENSG00000026103 UniProt: P25445 OMIM: 134637

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.443 OMIM phenotypes

Clinical Summary— FAS

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Gene-Disease Validity (ClinGen)

FAS-related autoimmune lymphoproliferative immune disorder · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

122 unique Pathogenic / Likely Pathogenic· 224 VUS of 527 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FAS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.812

Z-score 3.01

OE 0.14 (0.06–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.23Z-score

OE missense 0.73 (0.63–0.85)

121 obs / 165.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.44)

0≤0.351.4

Missense OE?0.73 (0.63–0.85)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 2 / 14.3Missense obs/exp: 121 / 165.6Syn Z: 0.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFAS-related autoimmune lymphoproliferative syndromeDNAD

definitiveFAS-related autoimmune lymphoproliferative syndromeDNAR

This gene — mechanism propensity

0.5770th %ile

GOF

0.7028th %ile

LOF

0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · 61% of P/LP variants are LoF · LOEUF 0.44

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNExtracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis.1

GOFMutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes.2

LOFWe have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploin1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

527 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic75

Likely Pathogenic47

VUS224

Likely Benign115

Benign42

Conflicting13

Pathogenic

Likely Pathogenic

224

VUS

115

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	52	18	5	0	75
Likely Pathogenic	22	20	5	0	47
VUS	6	186	30	2	224
Likely Benign	0	7	54	54	115
Benign	0	0	37	5	42
Conflicting	—				13
Total	80	231	131	61	516

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap FAS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

FAS · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — FAS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Breast Cancer

Anti-Inflammatory Diet in BRC Patients on Aromatase Inhibitors

RECRUITING

NCT06214598Phase NAUniversity of BelgradeStarted 2024-03-01

SupplementAI dietPlacebo

Alzheimer DiseaseAlzheimer Dementia

Daily Light and Sound Stimulation to Improve Brain Functions in Alzheimer's Disease

ACTIVE NOT RECRUITING

NCT04055376Phase NAMassachusetts Institute of TechnologyStarted 2019-08-14

GENUS device (Active Settings)GENUS device (Sham Settings)

Lung Cancer

Detection of Genetic Markers of Lung Cancer

RECRUITING

NCT00280202University of PittsburghStarted 1996-06

Biopsy of the major carinal areaBiopsy of abnormal & suspicious areas of the bronchial treeEvaluation of the tumor for DNA mutations

Cardiovascular Disease

Genes, Omega-3 Fatty Acids and Cardiovascular Disease Risk Factors

ACTIVE NOT RECRUITING

NCT01343342Phase NALaval UniversityStarted 2009-10

n-3 PUFA supplementation

Epidermolysis BullosaRecessive Dystrophic Epidermolysis BullosaRDEB

A Phase 3b Study for the Treatment of Dystrophic Epidermolysis Bullosa (DEB) in New and Previously EB-101 Treated Patients

ACTIVE NOT RECRUITING

NCT05725018Phase PHASE3Abeona Therapeutics, IncStarted 2023-04-02

EB-101 Surgical application of RDEB wounds

ResilienceCognitive Function and Well-BeingMuscle Function, Handgrip Strength Test

Aging Resilience Through Microbiota Optimization and Regulation

ACTIVE NOT RECRUITING

NCT06649981Phase PHASE1Gonzalo Jorquera, PhDStarted 2025-01-10

FMT capsulePlacebo Capsule(s)

Biliary Tract CancerColorectal CarcinomaGastric Cancer, Metastatic

CDH17 CAR-T Therapy in Advanced Malignant Solid Tumors

RECRUITING

NCT06937567Phase EARLY_PHASE1Zhejiang UniversityStarted 2024-12-26

CDH17 CAR-TFAST LACO-Stim CDH17 CAR-T

Metastatic Triple Negative Breast Cancer

To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.

ACTIVE NOT RECRUITING

NCT03330847Phase PHASE2AstraZenecaStarted 2018-03-07

Olaparib Continuous (28-Day cycle) 300 mg BD.Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).

NSCLC (Advanced Non-small Cell Lung Cancer)

Becotatug Vedotin Combined With Pucotenlimab ± Radiotherapy as First-Line Treatment for Driver-Gene-Negative, EGFR-Expression-Positive Advanced Non-Small Cell Lung Cancer

NOT YET RECRUITING

NCT07627321Phase PHASE2Anhui Provincial Cancer HospitalStarted 2026-07-15

PucotenlimabBecotatug vedotinRadiotherapy

Insulin SensitivityOverweight or ObesityInflammatory Response

Pulses Consumption and Its Role in Managing Systemic Inflammation, Insulin Sensitivity and Gut Microbiome in Human

ACTIVE NOT RECRUITING

NCT04267705Phase NAClinical Nutrition Research Center, Illinois Institute of TechnologyStarted 2020-02-24

ControlBlack beanChickpea

Neoplasms

A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

ACTIVE NOT RECRUITING

NCT04607421Phase PHASE3PfizerStarted 2020-12-21