GAN

Chr 16AR

gigaxonin

Also known as: GAN1, GIG, KLHL16

NCBI Gene: 8139 ENSG00000261609 UniProt: Q9H2C0 OMIM: 605379

The protein functions as a cytoskeletal component that maintains neurofilament architecture and acts as a substrate-specific adapter for ubiquitin-mediated degradation of neuronal proteins including MAP1B and TBCB. Mutations cause giant axonal neuropathy-1, a progressive neurodegenerative disorder that typically presents in early childhood with peripheral neuropathy and distinctive giant axons containing neurofilament accumulations. This condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Giant axonal neuropathy-1MIM #256850

Clinical highlights

Management implications

GAN has therapies in development

Gene–disease validity (ClinGen)

Definitive · giant axonal neuropathy 1 · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

2108

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.50

LOEUF

LOF

Mechanism· G2P

scAAV9/JeT-GAN
AAV gene therapyPhase 1
Intrathecal delivery of the GAN gene.
Delivery: Intrathecal

Therapeutic landscape as of 2026-07. Educational only. Investigational ≠ available; not medical advice or eligibility. Approved entries are precise; investigational program names/phases are conservative and move fast. Curated from FDA/EMA approvals and the clinical-trial literature; verify against current labeling + ClinicalTrials.gov.

ClinicalTrials.gov

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.025

Z-score 3.71

OE 0.29 (0.17–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.73Z-score

OE missense 1.11 (1.02–1.21)

367 obs / 329.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.29 (0.17–0.50)

0≤0.351.4

Missense OE?1.11 (1.02–1.21)

0≤0.61.4

Synonymous OE?1.55

0≤1.21.6

LoF obs/exp: 9 / 31.4Missense obs/exp: 367 / 329.9Syn Z: -4.74

Background carrier burden — how many people carry a rare variant somewhere in GAN?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 97

984 rare PASS variants

Rare truncating (LoF)

1 in 2,600

104 rare PASS variants

Rare synonymous (reference)

1 in 160

405 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GAN. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 2,400
South Asian	~43k	1 in 91	1 in 1,700
Remaining (unassigned)	~30k	1 in 90	1 in 5,000
European (Finnish)	~27k	1 in 130	1 in 2,200
Admixed American	~22k	1 in 110	1 in 1,100
African / African American	~21k	1 in 82	1 in 3,500
East Asian	~20k	1 in 83	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 240	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 11 coding exons well covered in gnomAD exomes; exons 2, 6, 10 marginal. Genomes: 10 of 11 (exon 9 below).? see exons ↓