FEM1C

protein-coding

fem-1 homolog C, the group of Ankyrin repeat domain containing

Gene summary

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_020177.3

Inheritance

ClinVar variants

P:1U:52B:2

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr5:115,520,908-115,544,775

External References & Databases

Ensembl (ENSG00000145780)

Transcript & Mutation Effects

hg38 • Region Span ~23.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: ClinGen

The *FEM1C* gene is located on chromosome 5 at 5q22.3, and codes for the FEM1 homolog C protein. This protein facilitates ubiquitin-resembling ligase-substrate adaptor function, and is key in ubiquitin-contingent protein catabolic processes through the C-end degron rule pathway. *FEM1C* was first reported in relation to autosomal dominant neurodevelopmental disorder in 2023 (Dubey et al., 2023 PMID: 36336956). Probands with this condition exhibit global developmental delay, moderate intellectual disability, pyramidal signs, ataxia, hypotonia, spasticity, ocular anomalies(including nystagmus and strabismus), and facial dysmorphisms (such as wide nasal bridge, malar hypoplasia, and posteriorly rotated ears). Two variants (both missense) that have been reported in two probands in one publication and a ClinVar submission are included in this curation (PMID: 36336956; and GeneDx/Illumina Laboratory internal data (ClinVar: SCV003802834)). The mechanism of pathogenicity appears to be loss of function (PMID: 36336956). No scorable experimental evidence was found. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 5/15/2026 (SOP Version 12).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FEM1C variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 47

not providedTotal: 4

Neurodevelopmental disorderTotal: 2

FEM1C-related intellectual disabilityTotal: 1

FEM1C-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020177.3. 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				1 clinvar	1 clinvar	2
missense		1 clinvar	52 clinvar			53
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	1	52	1	1	55

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020177.3	RefSeq	NP_064562.1	2	MANE Select
ENST00000274457.5	Ensembl	ENSP00000274457.3	2	MANE Select
ENST00000855971.1	Ensembl	ENSP00000526030.1	2	Standard
ENST00000855971.2	Ensembl	ENSP00000526030.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Neddylation

Biological Process

protein ubiquitination
post-translational protein modification

Molecular Function

protein binding

Cellular Component

nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274457
Coding exons: 2
Length: 23984
Individuals with no LoFs: 125651
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125658
p: 0.0000279

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.43	212	338	0.628	0.0000168	4082
Missense (PolyPhen)		42	135.89	0.30907		1644
Synonymous	0.404	121	127	0.954	0.00000662	1213
Loss of Function	3.04	3	16.2	0.185	8.58e-7	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable component of an E3 ubiquitin-protein ligase complex, in which it may act as a substrate recognition subunit. {ECO:0000250}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.365
RVIS EVS: -0.63
RVIS percentile EVS: 17.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.932

Gene Damage Prediction

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