# NM_001134831.2(AHI1):c.813A>G (p.Ser271=)

https://sugi.bio/variant/ahi1-p-ser271

## Summary

**AHI1 p.Ser271= (c.813A>G)** is classified **Likely benign** in AHI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). Very rare (popmax 0.00268%, afr); Associated with Joubert syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs771131198 · 1 submitter · 1 linked condition · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the AHI1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Joubert syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006802/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.Ser271= |
| Coding change (HGVS c.) | c.813A>G |
| MANE Select transcript | [NM_001134831](https://www.ncbi.nlm.nih.gov/nuccore/NM_001134831) |
| dbSNP | [rs771131198](https://www.ncbi.nlm.nih.gov/snp/rs771131198/) |
| Variant type | single nucleotide variant |
| Location | chr6:135463243-135463243 (GRCh38) |
| ClinVar | [VCV2887819](https://www.ncbi.nlm.nih.gov/clinvar/variation/2887819/) |

**All HGVS expressions:** `NC_000006.11:g.135784381T>C`, `NC_000006.12:g.135463243T>C`, `NG_008643.2:g.39523A>G`, `NM_001134830.2:c.813A>G`, `NM_001134831.2:c.813A>G`, `NM_001134832.2:c.813A>G`, `NM_001350503.2:c.813A>G`, `NM_001350504.2:c.813A>G`, `NM_017651.5:c.813A>G`

## 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 -0.16, GERP -3.67 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.878**. 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 (T>A, Δ0.54 acceptor gain), 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 **0.00268%** (afr) · FAF95 0.000446% · FAF99 0.000167% · 2/74,498 in the highest group · 3/1,610,946 alleles overall — very rare (popmax 0.00268%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00268% | 37,249 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,410 |

*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 **271** lies in the 'interaction with hap1' region; the 'disordered' region.

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.Ser271= falls in the interaction with hap1 region.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-09.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-09 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Joubert syndrome, CEREBELLOPARENCHYMAL DISORDER IV, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis.

## Same-residue context {#hotspot}

Residue **271** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AHI1 p.Ser271Ter](/variant/ahi1-p-ser271ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AHI1 variant pages (same residue, condition, or type): [AHI1 p.Ser271Ter](/variant/ahi1-p-ser271ter), [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.2623+1G>A](/variant/ahi1-c-2623-plus-1g-a), [AHI1 c.2623+1G>T](/variant/ahi1-c-2623-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2887819). 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.*