HEPHL1

protein-coding

hephaestin like 1

Gene summary

Enables ferroxidase activity. Involved in intracellular iron ion homeostasis. Predicted to be located in membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001098672.2

Inheritance

ClinVar variants

P:6U:189B:35

Top phenotype

Abnormal hair, joint laxity, and developmental delay

gnomAD constraint

pLI —, LoF o/e 0.94

Max pathogenic AF

—

Genomic locus

chr11:94,021,354-94,114,208

External References & Databases

Ensembl (ENSG00000181333)

Transcript & Mutation Effects

hg38 • Region Span ~92.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pili torti-developmental delay-neurological abnormalities syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009871

Submitter: ClinGen

*HEPHL1* was first reported in relation to autosomal dominant iron overload in 2015 (McDonald CM et al., PMID: PMID: 26151776) the p.Asp136Val variant mentioned in this study is found in 101 alleles including 1 homozygous in gnomAD V4 making it’s role unclear in the proband described. Biallelic *HEPHL1 *variants were later associated with a phenotype of pilli torti and developmental delay (Sharma P et al., PMID: 31125343). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism using the evidence provided by these papers. Therefore, the following disease entities have been lumped into one disease entities pili torti-developmental delay-neurological abnormalities syndrome. Two variants (one missense and one in-frame del, that have been reported in one probands in one publications (Sharma P et al., PMID: 31125343) are included in this curation. The mechanism of pathogenicity appears to be loss of function as both published variants reported resulted in non-detectable conversion of Fe (II) to Fe (III) indicating that that both mutants were catalytically inactive in the assay (Sharma P et al., PMID: 31125343). This gene-disease relationship is also supported by mouse models where Hephl1 knockout mouse model exhibited short, curled whiskers that was not found in Heterozygous mice (Zp+/-) models (Sharma P et al., PMID: 31125343). No additional neurological phenotypes were tested in these animal models according to the publication. In summary, there is limited evidence supporting the relationship between HEPHL1 and autosomal recessive pili torti-developmental delay-neurological abnormalities syndrome. This classification was approved by the ClinGen IEM GCEP on the meeting date February 14 (SOP Version 11).

pili torti-developmental delay-neurological abnormalities syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009871

Submitter: PanelApp Australia

pili torti-developmental delay-neurological abnormalities syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009871

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Abnormal hair, joint laxity, and developmental delayAR

Manifestation: Biochemical; Dermatologic; Musculoskeletal; 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: 31125343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HEPHL1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 201

not providedTotal: 22

HEPHL1-related disorderTotal: 13

Pili torti-developmental delay-neurological abnormalities syndromeTotal: 9

Lichen planopilarisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098672.2. 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				15 clinvar	3 clinvar	18
missense			184 clinvar	12 clinvar	5 clinvar	201
nonsense		3 clinvar	2 clinvar			5
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	0	6	189	27	8	230

Highest pathogenic variant AF is 0.00008738041

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001098672.2	RefSeq	NP_001092142.1	20	MANE Select
ENST00000315765.10	Ensembl	ENSP00000313699.9	20	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Iron metabolism in placenta

Biological Process

copper ion transport
iron ion transport
iron ion homeostasis
oxidation-reduction process

Molecular Function

ferroxidase activity
copper ion binding
oxidoreductase activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315765
Coding exons: 20
Length: 92391
Individuals with no LoFs: 124272
Homozygous LoFs: 1
Heterozygous LoFs: 378
Defined: 124651
p: 0.00152

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.184	622	635	0.979	0.0000326	7663
Missense (PolyPhen)		247	255.14	0.96809		3158
Synonymous	-0.606	248	236	1.05	0.0000131	2180
Loss of Function	0.409	54	57.3	0.942	0.00000334	646

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0043	0.0043	notable
Finnish	0.00098	0.00098	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.0021	0.0021	notable
Other	0.0025	0.0025	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a ferroxidase and may be involved in copper transport and homeostasis. {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.207
RVIS EVS: -0.28
RVIS percentile EVS: 33.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.269

Gene Damage Prediction

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