EPB41L1

protein-coding

erythrocyte membrane protein band 4.1 like 1, the group of Erythrocyte membrane protein band 4.1|FERM domain containing

Gene summary

Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

MANE transcript

NM_012156.2

Inheritance

ClinVar variants

P:1U:126B:70

Top phenotype

Intellectual developmental disorder, autosomal dominant 11

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr20:36,091,504-36,232,799

External References & Databases

Ensembl (ENSG00000088367)

Transcript & Mutation Effects

hg38 • Region Span ~141.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual disability, autosomal dominant 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013658

Submitter: G2P

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*EPB41L1* encodes a neuronal cytoskeletal protein that mediates interactions between the cytoskeleton and membrane proteins including synaptic receptors. *EPB41L1* was first reported in relation to autosomal dominant non-syndromic intellectual disability (ID) in 2011 (Hamdan et al., PMID: 21376300). Hamdan et al. reported a *de novo* missense variant in an individual with severe ID and hypotonia with normal brain MRI. Functional studies revealed reduced binding of EPB41L1 to AMPA glutamate receptors, resulting in decreased receptor trafficking at the synaptic membrane (PMID: 21376300). At least five additional missense variants have been reported in exome sequencing studies in individuals with autism spectrum disorder or developmental disorders, four of which were *de novo* (PMIDs: 24467814, 25961944, 28344757, 33057194). These variants affect highly conserved positions and are predicted deleterious with various pathogenicity tools, but only two are absent from gnomAD; in the absence of functional studies they were not scored. A splice variant of unknown inheritance in a proband with autism (PMID: 31981491) was present 10 times in gnomAD v4.1.1, and was therefore not added as evidence. Large 20q11.2 deletions (>1.6 Mb) encompassing *EPB41L1* have been reported in individuals with ID, craniofacial dysmorphism, and anomalies of the extremities (PMID: 25572454). However, this evidence is insufficient to support pathogenicity due to *EPB41L1* haploinsufficiency. *EPB41L1* is intolerant to truncating variants (pLI = 1, LOEUF = 0.4; gnomAD v4.1.1) and missense variants (Z = 4.38). Since only one missense variant in *EPB41L1* has been reported in non-syndromic ID, we decided to curate for the more general term complex neurodevelopmental disorder. This gene-disease relationship is also supported by protein interactions with AMPA glutamate receptors implicated in ID and other neurodevelopmental disorders (GRIA1 and GRIA4). However, given the paucity of genetic evidence, this experimental evidence was not scored. In summary, there is limited evidence to support the relationship between *EPB41L1* and autosomal dominant complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 6, 2022. It was reevaluated on August 24, 2026. As a result of this reevaluation, no additional patients were identified and the classification did not change. The scoring was updated to be consistent with SOP Version 12.

intellectual disability, autosomal dominant 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013658

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 11AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21376300

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPB41L1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 160

not providedTotal: 56

Intellectual disability, autosomal dominant 11Total: 17

EPB41L1-related disorderTotal: 11

Intellectual disabilityTotal: 3

Complex neurodevelopmental disorderTotal: 2

Abnormal brain morphologyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012156.2. 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			2 clinvar	37 clinvar	5 clinvar	44
missense		1 clinvar	118 clinvar	25 clinvar	2 clinvar	146
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			5 clinvar	1 clinvar		6
Total	0	1	126	63	7	197

Highest pathogenic variant AF is 0.000008054563

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 234 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012156.2	RefSeq	NP_036288.2	21	MANE Select
ENST00000338074.7	Ensembl	ENSP00000337168.2	21	MANE Select
NM_001258329.1	RefSeq	NP_001245258.1	21	Standard
NM_001258330.1	RefSeq	NP_001245259.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Splicing factor NOVA regulated synaptic proteins
Neuronal System
Neurexins and neuroligins
Trafficking of AMPA receptors
Glutamate binding, activation of AMPA receptors and synaptic plasticity

Biological Process

cortical actin cytoskeleton organization
actomyosin structure organization

Molecular Function

actin binding
structural molecule activity
protein binding

Cellular Component

cytosol
cytoskeleton
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338074
Coding exons: 21
Length: 141296
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.94	394	518	0.760	0.0000337	5781
Missense (PolyPhen)		116	216.23	0.53647		2487
Synonymous	1.73	183	215	0.850	0.0000143	1743
Loss of Function	4.87	8	42.1	0.190	0.00000207	516

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function to confer stability and plasticity to neuronal membrane via multiple interactions, including the spectrin-actin-based cytoskeleton, integral membrane channels and membrane-associated guanylate kinases.;

Recessive Scores

pRec: 0.0936

Intolerance Scores

LoFtool: 0.0449
RVIS EVS: -0.73
RVIS percentile EVS: 14.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.839

Gene Damage Prediction

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