AHI1

Chr 6AR

Abelson helper integration site 1

Also known as: AHI-1, JBTS3, ORF1, dJ71N10.1

NCBI Gene: 54806ENSG00000135541UniProt: Q8N157

This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Joubert syndrome 3MIM #608629
AR
1828
ClinVar variants
96
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— AHI1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
96 Pathogenic / Likely Pathogenic· 208 VUS of 1828 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.95LOEUF
pLI 0.000
Z-score 1.88
OE 0.75 (0.59–0.95)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.03Z-score
OE missense 1.00 (0.94–1.07)
598 obs / 595.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.75 (0.59–0.95)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.94–1.07)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 48 / 64.3Missense obs/exp: 598 / 595.6Syn Z: -0.48

ClinVar Variant Classifications

1828 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic50
VUS208
Likely Benign151
Benign1
Conflicting13
46
Pathogenic
50
Likely Pathogenic
208
VUS
151
Likely Benign
1
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
0
31
0
46
Likely Pathogenic
40
2
8
0
50
VUS
0
174
30
4
208
Likely Benign
0
4
69
78
151
Benign
0
0
1
0
1
Conflicting
—13
Total5518013982469

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

View in ClinVar →

Protein Context — Lollipop Plot

AHI1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AHI1-related Joubert syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Joubert syndrome 3

MIM #608629

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genotype-phenotype correlates in Joubert syndrome: A review.
Gana S et al.·Am J Med Genet C Semin Med Genet
2022Review
Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing.
Huang XF et al.·Genet Med
2015Cohort
Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.
Aksu Uzunhan T et al.·Clin Neurol Neurosurg
2023
Identification of a novel truncating variant in AHI1 gene and a brief review on mutations spectrum.
Karamzade A et al.·Mol Biol Rep
2021Review
Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency.
Bronson PG et al.·Nat Genet
2016Meta-analysis
Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders.
Radha Rama Devi A et al.·Pediatr Neurol
2020
DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands.
Kroes HY et al.·Eur J Med Genet
2008Cohort
Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants.
Chen C et al.·BMC Med Genomics
2021Case report
Optical Genome Mapping Reveals Novel Structural Variants in Lymphoblastic Lymphoma.
Xu H et al.·J Pediatr Hematol Oncol
2024
Joubert syndrome and related disorders.
Paprocka J et al.·Neurol Neurochir Pol
2012Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Gestational diabetes mellitus induces 5-HT system dysfunction and exacerbates an ASD-like phenotype in male offspring by inhibiting the Ahi1/B9D1/Shh axis.
Qin G et al.·Brain Behav Immun
2025
Blended Phenotypes of Sexual Development Disorder and Coenzyme Q10 Deficiency, Together with a Sibling with Homozygous Variants in the AHI1 Gene.
Atasay R et al.·Mol Syndromol
2025
GR/Ahi1 regulates WDR68-DYRK1A binding and mediates cognitive impairment in prenatally stressed offspring.
Wei B et al.·Cell Mol Life Sci
2024
Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.
Downie ML et al.·Kidney Int Rep
2023🔓 Open Access
The mitochondrial Ahi1/GR participates the regulation on mtDNA copy numbers and brain ATP levels and modulates depressive behaviors in mice.
Wang B et al.·Cell Commun Signal
2023🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
PSC

Colangioids to Define the Genetic Factors Involved in Atypical Primary Sclerosing Cholangitis

ACTIVE NOT RECRUITING
NCT06865924Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2024-12-01
Use of assembloids as in vitro models to test new pharmacological approaches

External Resources

Links to major genomics databases and tools