# NM_000541.5(SAG):c.1137del (p.Phe379fs)

https://sugi.bio/variant/sag-p-phe379fs

## Summary

**SAG p.Phe379fs (c.1137del)** is classified **Uncertain significance** in SAG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-11). Very rare (popmax 8.49e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the SAG gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [SAG](https://sugi.bio/atlas/gene/SAG/) |
| Protein change (HGVS p.) | p.Phe379fs |
| Coding change (HGVS c.) | c.1137del |
| MANE Select transcript | [NM_000541](https://www.ncbi.nlm.nih.gov/nuccore/NM_000541) |
| Variant type | Deletion |
| Location | chr2:233346827-233346827 (GRCh38) |
| ClinVar | [VCV4960659](https://www.ncbi.nlm.nih.gov/clinvar/variation/4960659/) |

**All HGVS expressions:** `NC_000002.11:g.234255477del`, `NC_000002.12:g.233346831del`, `NG_009116.1:g.44169del`, `NM_000541.5:c.1137del`

## 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 9.787, GERP 1.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- 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.
- Population frequency (gnomAD v4.1): grpmax **8.49e-05%** (nfe) · 1/1,177,814 in the highest group · 1/1,610,886 alleles overall — very rare (popmax 8.49e-05%, nfe).

*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}


Curated gene–disease validity (ClinGen):

- **retinitis pigmentosa 47** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.02, 59% of residues very-high.

**7 experimental structure(s)** (PDB): [2ECL](https://www.rcsb.org/structure/2ECL), [7ONI](https://www.rcsb.org/structure/7ONI), [9EG1](https://www.rcsb.org/structure/9EG1), [9OMA](https://www.rcsb.org/structure/9OMA), [9SDX](https://www.rcsb.org/structure/9SDX), [9SDY](https://www.rcsb.org/structure/9SDY) — incl. mutant structure 9SDX.

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

*Describes the biological roles of SAG (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:** SAG's established molecular role includes ubiquitin protein ligase activity.


### Pathways affected {#pathways}

SAG participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Inactivation of CSF3 (G-CSF) signaling](https://reactome.org/content/detail/R-HSA-9705462) | electronic |

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

**Molecular function:** ubiquitin protein ligase activity, NEDD8 ligase activity, cullin family protein binding.

**Biological process:** endoplasmic reticulum unfolded protein response, proteasome-mediated ubiquitin-dependent protein catabolic process, protein neddylation, negative regulation of focal adhesion assembly, protein K11-linked ubiquitination.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-11.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related SAG variant pages (same residue, condition, or type): [SAG p.Phe379Ser](/variant/sag-p-phe379ser), [SAG c.72_75+15del](/variant/sag-c-72-75-plus-15del), [SAG p.Asn309fs](/variant/sag-p-asn309fs), [SAG p.Asp374fs](/variant/sag-p-asp374fs), [SAG p.Asn232fs](/variant/sag-p-asn232fs), [SAG p.Gln93fs](/variant/sag-p-gln93fs), [SAG p.Glu270fs](/variant/sag-p-glu270fs), [SAG p.Leu207fs](/variant/sag-p-leu207fs).

### 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 4960659). 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.*