# NM_001378454.1(ALMS1):c.1671del (p.Pro558fs)

https://sugi.bio/variant/alms1-p-pro558fs

## Summary

**ALMS1 p.Pro558fs (c.1671del)** is classified **Likely pathogenic** in ALMS1 (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs786205633 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ALMS1 gene that is considered likely disease-causing, submitted by 1 submitter.

*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 | [ALMS1](https://sugi.bio/atlas/gene/ALMS1/) |
| Protein change (HGVS p.) | p.Pro558fs |
| Coding change (HGVS c.) | c.1671del |
| MANE Select transcript | [NM_001378454](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378454) |
| dbSNP | [rs786205633](https://www.ncbi.nlm.nih.gov/snp/rs786205633/) |
| Variant type | Deletion |
| Location | chr2:73448197-73448197 (GRCh38) |
| ClinVar | [VCV191303](https://www.ncbi.nlm.nih.gov/clinvar/variation/191303/) |

**All HGVS expressions:** `LRG_741:g.67446del`, `LRG_741t1:c.1674del`, `NC_000002.11:g.73675325del`, `NC_000002.12:g.73448198del`, `NG_011690.1:g.67446del`, `NM_001378454.1:c.1671del`, `NM_015120.4:c.1674del`

## 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 -1.847, GERP -3.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.825, pLI 2.1295e-65. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** (CAGATAGTCATCTAACTGAAGAGGCTCTGAAAGTTTCAGCTGTTCCTGGACCAGCTGACCAGAAGACTGGCATACCAACTGTAACCTCTACTTCCTACTCACATAGAGAGAAGCCTAGTATTTTCTACCAACAGGCCTTGC, TCATCTAACTGAAGAGGCTCTGAAAATTTCAGTAGTCCTGGACCAGCTGACCAGAAGACTGGCACACCAACTGTAACCTCTACTTCCTACTCACAACAGAGAGAAGCCCAGCATTTTCTACCAACAGGCGTTGCCAAGTAGTCATCTAACTGAAGAGGCTCAGAAAGTTTCAGCGGTTCCTGGACCAGCTGACCAGAAGACTGTGATACCAACAGTACCCTCTACCTTCTACTCACAAAGAGAGAAGCCTAGTGTTTTCTACCAACAGGCCTTGCCAGATAGTCATCCAACTGAAGAGGCTCTGAAAGTTTCAGTTGCTCTGGACCAGCTGACCAGACAACTGGCACACCAACTGTAACCTCTACTTCTTACTCACACAACAGAGAAGCCTGGTATTTTCTACCAACAGTCTTGCCAGGTAG). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- 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}

**ALMS1** population constraint: LOEUF 0.825, pLI 2.1295e-65, missense-Z -1.692; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **Alstrom syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **558** lies in the '34 x 47 aa approximate tandem repeat' region; the 'disordered' region.

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

*Describes the biological roles of ALMS1 (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.*


### Pathways affected {#pathways}

ALMS1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

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

**Biological process:** endosomal transport, regulation of stress fiber assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | research |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related ALMS1 variant pages (same residue, condition, or type): [ALMS1 p.Pro558=](/variant/alms1-p-pro558), [ALMS1 c.1432+2_1432+15del](/variant/alms1-c-1432-plus-2-1432-plus-15del), [ALMS1 c.9782-1269_9859del](/variant/alms1-c-9782-minus-1269-9859del), [ALMS1 p.Ala1083fs](/variant/alms1-p-ala1083fs), [ALMS1 p.Ala1515fs](/variant/alms1-p-ala1515fs), [ALMS1 p.Ala3307fs](/variant/alms1-p-ala3307fs), [ALMS1 p.Ala50fs](/variant/alms1-p-ala50fs), [ALMS1 p.Arg1417fs](/variant/alms1-p-arg1417fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 191303). 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.*