# NM_014363.6(SACS):c.2776A>G (p.Ile926Val)

https://sugi.bio/variant/sacs-p-ile926val

## Summary

**SACS p.Ile926Val (c.2776A>G)** is classified **Conflicting classifications of pathogenicity** in SACS (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0793); Rare (popmax 0.66%, mid); Associated with Spastic paraplegia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144362131 · 7 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.66%, mid)

## For patients & families {#patients}

This is a change in the SACS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Spastic paraplegia.

*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 | [SACS](https://sugi.bio/atlas/gene/SACS/) |
| Protein change (HGVS p.) | p.Ile926Val |
| Coding change (HGVS c.) | c.2776A>G |
| MANE Select transcript | [NM_014363](https://www.ncbi.nlm.nih.gov/nuccore/NM_014363) |
| dbSNP | [rs144362131](https://www.ncbi.nlm.nih.gov/snp/rs144362131/) |
| Variant type | single nucleotide variant |
| Location | chr13:23341100-23341100 (GRCh38) |
| ClinVar | [VCV586429](https://www.ncbi.nlm.nih.gov/clinvar/variation/586429/) |

**All HGVS expressions:** `NC_000013.10:g.23915239T>C`, `NC_000013.11:g.23341100T>C`, `NG_012342.1:g.97603A>G`, `NM_001278055.2:c.2335A>G`, `NM_014363.6:c.2776A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0793)
- REVEL 0.275 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 0.47, GERP 0.831, phastCons 0.368 — weakly conserved position
- CADD: **PHRED 15.62**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (23,335,277–23,411,239), spanning 75,962 bp. Chi-square p 0.00012. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.66%** (mid) · FAF95 0.498% · FAF99 0.442% · 40/6,062 in the highest group · 175/1,613,850 alleles overall — rare (popmax 0.66%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.66% | 152 |
| Admixed American | 0.04% | 2,501 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0338% | 2,960 |
| Remaining individuals (not grpmax-eligible) | 0.0272% | 3,677 |
| East Asian | 0.00891% | 11,218 |
| European (non-Finnish) | 0.00636% | 15,733 |
| South Asian | 0.00439% | 22,767 |
| African / African-American | 0.00133% | 75,068 |

*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 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.*

## Protein context {#protein}


**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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-24.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 likely benign, 1 Likely benign).

**Submission history:** 7 submissions (2018–2025); 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 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-09-16 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-06-01 |
| Athena Diagnostics | likely benign | criteria provided, single submitter | clinical testing | 2024-09-24 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Spastic paraplegia, Charlevoix-Saguenay spastic ataxia, Hereditary spastic paraplegia, not specified, SPASTIC ATAXIA 6, AUTOSOMAL RECESSIVE, AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF CHARLEVOIX-SAGUENAY, Spastic ataxia of Charlevoix-Saguenay, AllHighlyPenetrant, Familial spastic paraparesis.

## Similar variants {#similar}

Related SACS variant pages (same residue, condition, or type): [SACS c.2093+1G>A](/variant/sacs-c-2093-plus-1g-a), [SACS c.604+1G>A](/variant/sacs-c-604-plus-1g-a), [SACS p.Ala4074Pro](/variant/sacs-p-ala4074pro), [SACS p.Arg1575Pro](/variant/sacs-p-arg1575pro), [SACS p.Arg1645Gln](/variant/sacs-p-arg1645gln), [SACS p.Arg1645Ter](/variant/sacs-p-arg1645ter), [SACS p.Arg1877Ter](/variant/sacs-p-arg1877ter), [SACS p.Arg1907Ter](/variant/sacs-p-arg1907ter).

### 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 586429). 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.*