# NM_014363.6(SACS):c.896_898delinsCT (p.Phe299fs)

https://sugi.bio/variant/sacs-p-phe299fs

## Summary

**SACS p.Phe299fs (c.896_898delinsCT)** is classified **Likely pathogenic** in SACS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). No gnomAD frequency available for this variant; Associated with Charlevoix-Saguenay spastic ataxia.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2542401788 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SACS gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Charlevoix-Saguenay spastic ataxia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SACS is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Autosomal recessive spastic ataxia of Charlevoix-Saguenay** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Urinary incontinence — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Cerebellar atrophy — Frequent (79-30%)
- Dysmetria — Frequent (79-30%)
- Abnormal cerebellum morphology — Frequent (79-30%)
- Cerebellar vermis hypoplasia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004910/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SACS](https://sugi.bio/atlas/gene/SACS/) |
| Protein change (HGVS p.) | p.Phe299fs |
| Coding change (HGVS c.) | c.896_898delinsCT |
| MANE Select transcript | [NM_014363](https://www.ncbi.nlm.nih.gov/nuccore/NM_014363) |
| dbSNP | [rs2542401788](https://www.ncbi.nlm.nih.gov/snp/rs2542401788/) |
| Variant type | Indel |
| Location | chr13:23355714-23355716 (GRCh38) |
| ClinVar | [VCV2678575](https://www.ncbi.nlm.nih.gov/clinvar/variation/2678575/) |

**All HGVS expressions:** `NC_000013.10:g.23929853_23929855delinsAG`, `NC_000013.11:g.23355714_23355716delinsAG`, `NG_012342.1:g.82987_82989delinsCT`, `NM_001278055.2:c.455_457delinsCT`, `NM_014363.6:c.896_898delinsCT`

## 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 0.466, GERP -2.64, phastCons 0.014 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.644, pLI 1.0713e-30. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**SACS** population constraint: LOEUF 0.644, pLI 1.0713e-30, missense-Z 3.0242; 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.*

## Protein context {#protein}

Residue **299** lies in an α-helix.

**7 experimental structure(s)** (PDB): [1IUR](https://www.rcsb.org/structure/1IUR), [3O10](https://www.rcsb.org/structure/3O10), [5V44](https://www.rcsb.org/structure/5V44), [5V45](https://www.rcsb.org/structure/5V45), [5V46](https://www.rcsb.org/structure/5V46), [5VSX](https://www.rcsb.org/structure/5VSX) — incl. mutant structure 5V45.

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

*Describes the biological roles of SACS (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:** SACS's established molecular role includes Hsp70 protein binding.


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

**Molecular function:** Hsp70 protein binding, identical protein binding, low-density lipoprotein particle receptor binding, protein-folding chaperone binding, proteasome binding.

**Biological process:** negative regulation of inclusion body assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-14 |

## Associated conditions {#conditions}

[Charlevoix-Saguenay spastic ataxia](https://sugi.bio/atlas/disease/charlevoix-saguenay-spastic-ataxia/).

**Reported phenotype names (ClinVar):** Charlevoix-Saguenay spastic ataxia, AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF CHARLEVOIX-SAGUENAY, Spastic ataxia of Charlevoix-Saguenay, SPASTIC ATAXIA 6, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related SACS variant pages (same residue, condition, or type): [SACS p.Asn3487_Leu3488delinsLysIle](/variant/sacs-p-asn3487-leu3488delinslysile), [SACS p.Ala155fs](/variant/sacs-p-ala155fs), [SACS p.Arg730fs](/variant/sacs-p-arg730fs), [SACS p.Glu2745fs](/variant/sacs-p-glu2745fs), [SACS p.Gly2090Ter](/variant/sacs-p-gly2090ter), [SACS p.Gly65fs](/variant/sacs-p-gly65fs), [SACS p.His1227Ter](/variant/sacs-p-his1227ter), [SACS p.Leu3525Ter](/variant/sacs-p-leu3525ter).

### 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 2678575). 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.*