# NM_001134831.2(AHI1):c.1788T>C (p.Arg596=)

https://sugi.bio/variant/ahi1-p-arg596

## Summary

**AHI1 p.Arg596= (c.1788T>C)** is classified **Conflicting classifications of pathogenicity** in AHI1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0225%, nfe); Associated with Joubert syndrome 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs548478362 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0225%, nfe)

## For patients & families {#patients}

This is a change in the AHI1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Joubert syndrome 3.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015435/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AHI1](https://sugi.bio/atlas/gene/AHI1/) |
| Protein change (HGVS p.) | p.Arg596= |
| Coding change (HGVS c.) | c.1788T>C |
| MANE Select transcript | [NM_001134831](https://www.ncbi.nlm.nih.gov/nuccore/NM_001134831) |
| dbSNP | [rs548478362](https://www.ncbi.nlm.nih.gov/snp/rs548478362/) |
| Variant type | single nucleotide variant |
| Location | chr6:135442706-135442706 (GRCh38) |
| ClinVar | [VCV355506](https://www.ncbi.nlm.nih.gov/clinvar/variation/355506/) |

**All HGVS expressions:** `NC_000006.11:g.135763844A>G`, `NC_000006.12:g.135442706A>G`, `NG_008643.2:g.60060T>C`, `NM_001134830.2:c.1788T>C`, `NM_001134831.2:c.1788T>C`, `NM_001134832.2:c.1788T>C`, `NM_001350503.2:c.1788T>C`, `NM_001350504.2:c.1788T>C`, `NM_017651.5:c.1788T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.942, GERP -5.66, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.832**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.32 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0225%** (nfe) · FAF95 0.0203% · FAF99 0.0194% · 265/1,176,406 in the highest group · 271/1,604,694 alleles overall — ultra-rare (popmax 0.0225%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0225% | 4,439 |
| Remaining individuals (not grpmax-eligible) | 0.00966% | 10,349 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AHI1** population constraint: LOEUF 1.069, pLI 2.6598e-30, missense-Z -0.22863; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Joubert syndrome 3** — Definitive (AR)

## Protein context {#protein}

Residue **596** lies in a UniProt-annotated variant site (in jbts3).

AlphaFold model confidence (whole protein): pLDDT 62.03, 18% of residues very-high.

**1 experimental structure(s)** (PDB): [4ESR](https://www.rcsb.org/structure/4ESR).

## What this gene does {#gene-function}

*Describes the biological roles of AHI1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AHI1's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

AHI1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-12.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-09 |

## Associated conditions {#conditions}

[Joubert syndrome 3](https://sugi.bio/atlas/disease/joubert-syndrome-3/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/).

**Reported phenotype names (ClinVar):** Joubert syndrome 3, Joubert syndrome, not specified, AHI1-related Ciliopathy, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis, AllHighlyPenetrant.

## Similar variants {#similar}

Related AHI1 variant pages (same residue, condition, or type): [AHI1 p.Arg596Cys](/variant/ahi1-p-arg596cys), [AHI1 p.Arg596His](/variant/ahi1-p-arg596his), [AHI1 c.1152-1G>A](/variant/ahi1-c-1152-minus-1g-a), [AHI1 c.1152-2A>G](/variant/ahi1-c-1152-minus-2a-g), [AHI1 c.1626+1G>A](/variant/ahi1-c-1626-plus-1g-a), [AHI1 c.1779+1G>T](/variant/ahi1-c-1779-plus-1g-t), [AHI1 c.2492+1G>A](/variant/ahi1-c-2492-plus-1g-a), [AHI1 c.2493-2A>G](/variant/ahi1-c-2493-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 355506). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*