ELOVL4

Chr 6ARAD

ELOVL fatty acid elongase 4

Also known as: ADMD, CT118, ISQMR, SCA34, STGD2, STGD3

NCBI Gene: 6785 ENSG00000118402 UniProt: Q9GZR5 OMIM: 605512

The protein catalyzes the rate-limiting step in very long-chain fatty acid elongation, synthesizing saturated and polyunsaturated fatty acids that serve as precursors for membrane lipids critical in early brain and skin development. Mutations cause autosomal dominant Stargardt disease 3 (retinal dystrophy), autosomal recessive spinocerebellar ataxia 34, and autosomal recessive ichthyosis with spastic quadriplegia and intellectual disability. The gene is highly constrained against loss-of-function variants, reflecting its essential role in neurodevelopment and retinal function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a membrane-bound protein which is a member of the ELO family, proteins which participate in the biosynthesis of fatty acids. Consistent with the expression of the encoded protein in photoreceptor cells of the retina, mutations and small deletions in this gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.413 OMIM phenotypes

Clinical Summary— ELOVL4

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Gene-Disease Validity (ClinGen)

ELOVL4-related maculopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.

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ClinVar Variants

29 unique Pathogenic / Likely Pathogenic· 180 VUS of 358 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.832

Z-score 3.41

OE 0.16 (0.07–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.19Z-score

OE missense 0.74 (0.64–0.86)

126 obs / 169.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.07–0.41)

0≤0.351.4

Missense OE?0.74 (0.64–0.86)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 3 / 19.1Missense obs/exp: 126 / 169.4Syn Z: -0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveELOVL4-related ichthyosis, spastic quadriplegia, and intellectual developmental disorderLOFAR

definitiveELOVL4-related Stargardt diseaseLOFAD

This gene — mechanism propensity

0.6065th %ile

GOF

0.5954th %ile

LOF

0.48top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF72% of P/LP variants are LoF · LOEUF 0.41

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNPathogenic mutations found in the ELOVL4 gene result in altered trafficking of the protein and behave with a dominant negative effect.1

GOFWe showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells.2

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

358 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic11

VUS180

Likely Benign102

Benign34

Conflicting11

Pathogenic

Likely Pathogenic

180

VUS

102

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	2	2	0	18
Likely Pathogenic	7	3	1	0	11
VUS	3	133	42	2	180
Likely Benign	0	2	37	63	102
Benign	0	1	33	0	34
Conflicting	—				11
Total	24	141	115	65	356

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap ELOVL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →