RFFL

protein-coding

ring finger and FYVE like domain containing E3 ubiquitin protein ligase, the group of Ring finger proteins

Gene summary

Enables enzyme binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in negative regulation of signal transduction; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein K48-linked ubiquitination. Located in endosome membrane and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001017368.2

Inheritance

—

ClinVar variants

U:40B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr17:35,005,990-35,089,319

External References & Databases

Ensembl (ENSG00000092871)

Transcript & Mutation Effects

hg38 • Region Span ~83.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFFL variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 41

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001017368.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense			40 clinvar	1 clinvar	2 clinvar	43
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	40	1	2	43

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001017368.2	RefSeq	NP_001017368.1	6	MANE Select
ENST00000394597.7	Ensembl	ENSP00000378096.3	6	MANE Select
ENST00000315249.11	Ensembl	ENSP00000326170.7	6	Standard
ENST00000315249.12	Ensembl	ENSP00000326170.7	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TNF alpha Signaling Pathway
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Regulation of TP53 Degradation

Biological Process

ubiquitin-dependent protein catabolic process
apoptotic process
regulation of fibroblast migration
negative regulation of tumor necrosis factor-mediated signaling pathway
regulation of TOR signaling

Molecular Function

protease binding
p53 binding
protein binding
protein kinase binding
ubiquitin protein ligase binding

Cellular Component

Golgi membrane
tumor necrosis factor receptor superfamily complex
nucleoplasm
cytoplasm
lysosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315249
Coding exons: 6
Length: 83330
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125747
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	149	205	0.726	0.0000113	2373
Missense (PolyPhen)		63	84.19	0.74831		1003
Synonymous	1.02	65	76.4	0.851	0.00000381	709
Loss of Function	3.08	4	18.2	0.220	0.00000101	197

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000099	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Mediates 'Lys-48'-linked polyubiquitination of PRR5L and its subsequent proteasomal degradation thereby indirectly regulating cell migration through the mTORC2 complex. Ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate cell death downstream of death domain receptors in the extrinsic pathway of apoptosis. Negatively regulates the tumor necrosis factor-mediated signaling pathway through targeting of RIPK1 to ubiquitin-mediated proteasomal degradation. Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation. Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN. May also play a role in endocytic recycling. {ECO:0000269|PubMed:15069192, ECO:0000269|PubMed:17121812, ECO:0000269|PubMed:18382127, ECO:0000269|PubMed:18450452, ECO:0000269|PubMed:22609986}.;

Recessive Scores

pRec: 0.0967

Intolerance Scores

LoFtool: 0.567
RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.883

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium