# NM_001134831.2(AHI1):c.3303dup (p.Pro1102fs)

https://sugi.bio/variant/ahi1-p-pro1102fs

## Summary

**AHI1 p.Pro1102fs (c.3303dup)** is classified **Pathogenic/Likely pathogenic** in AHI1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-12). No gnomAD frequency available for this variant; Associated with AHI1-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2128384496 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AHI1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to AHI1-related disorder.

*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:** [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.Pro1102fs |
| Coding change (HGVS c.) | c.3303dup |
| MANE Select transcript | [NM_001134831](https://www.ncbi.nlm.nih.gov/nuccore/NM_001134831) |
| dbSNP | [rs2128384496](https://www.ncbi.nlm.nih.gov/snp/rs2128384496/) |
| Variant type | Duplication |
| Location | chr6:135323186-135323187 (GRCh38) |
| ClinVar | [VCV1452728](https://www.ncbi.nlm.nih.gov/clinvar/variation/1452728/) |

**All HGVS expressions:** `NC_000006.11:g.135644328dup`, `NC_000006.12:g.135323190dup`, `NG_008643.2:g.179579dup`, `NM_001134830.2:c.3303dup`, `NM_001134831.2:c.3303dup`, `NM_001350503.2:c.3303dup`, `NM_001350504.2:c.3303dup`, `NM_017651.5:c.3303dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.817, GERP 2.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.069, pLI 2.6598e-30. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 25 of 29**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **1102** lies in a UniProt-annotated variant site (in jbts3); a β-strand; the sh3 domain.

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. p.Pro1102fs falls in the sh3 domain.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-09-12.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2020–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-12 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-11-12 |

## Associated conditions {#conditions}

[AHI1-related disorder](https://sugi.bio/atlas/disease/ahi1-related-disorder/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/).

**Reported phenotype names (ClinVar):** AHI1-related disorder, Joubert syndrome, AHI1-related condition, Familial aplasia of the vermis, JOUBERT-BOLTSHAUSER SYNDROME.

## Similar variants {#similar}

Related AHI1 variant pages (same residue, condition, or type): [AHI1 p.Arg235fs](/variant/ahi1-p-arg235fs), [AHI1 p.Asn1020fs](/variant/ahi1-p-asn1020fs), [AHI1 p.Cys614fs](/variant/ahi1-p-cys614fs), [AHI1 p.Leu33fs](/variant/ahi1-p-leu33fs), [AHI1 p.Leu37fs](/variant/ahi1-p-leu37fs), [AHI1 p.Leu413fs](/variant/ahi1-p-leu413fs), [AHI1 p.Leu750fs](/variant/ahi1-p-leu750fs), [AHI1 p.Thr304fs](/variant/ahi1-p-thr304fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1452728). 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.*