# NM_004318.4(ASPH):c.1173GAG[1] (p.Arg393del)

https://sugi.bio/variant/asph-p-arg393del

## Summary

**ASPH p.Arg393del (c.1173GAG[1])** is classified **Uncertain significance** in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). Very rare (popmax 0.00769%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs774306827 · 1 submitter · very rare (popmax 0.00769%, sas)

## For patients & families {#patients}

This is a change in the ASPH 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 | [ASPH](https://sugi.bio/atlas/gene/ASPH/) |
| Protein change (HGVS p.) | p.Arg393del |
| Coding change (HGVS c.) | c.1173GAG[1] |
| MANE Select transcript | [NM_004318](https://www.ncbi.nlm.nih.gov/nuccore/NM_004318) |
| dbSNP | [rs774306827](https://www.ncbi.nlm.nih.gov/snp/rs774306827/) |
| Variant type | Microsatellite |
| Location | chr8:61567290-61567292 (GRCh38) |
| ClinVar | [VCV3007500](https://www.ncbi.nlm.nih.gov/clinvar/variation/3007500/) |

**All HGVS expressions:** `NC_000008.10:g.62479849CTC[1]`, `NC_000008.11:g.61567290CTC[1]`, `NG_013210.1:g.152346GAG[1]`, `NM_001164750.2:c.1086GAG[1]`, `NM_001413844.1:c.1173GAG[1]`, `NM_001413845.1:c.1218GAG[1]`, `NM_001413846.1:c.1215GAG[1]`, `NM_001413847.1:c.1116GAG[1]`, `NM_001413848.1:c.1176GAG[1]`, `NM_001413849.1:c.1173GAG[1]`, `NM_001413850.1:c.1170GAG[1]`, `NM_001413851.1:c.1170GAG[1]`, `NM_001413852.1:c.1161GAG[1]`, `NM_001413853.1:c.1158GAG[1]`, `NM_001413854.1:c.1131GAG[1]`, `NM_001413855.1:c.1131GAG[1]`, `NM_001413856.1:c.1131GAG[1]`, `NM_001413857.1:c.1128GAG[1]`, `NM_001413858.1:c.1125GAG[1]`, `NM_001413859.1:c.1044GAG[1]`, `NM_001413860.1:c.1116GAG[1]`, `NM_001413861.1:c.1113GAG[1]`, `NM_001413862.1:c.1098GAG[1]`, `NM_001413863.1:c.1089GAG[1]`, `NM_001413864.1:c.1086GAG[1]`, `NM_001413865.1:c.1086GAG[1]`, `NM_001413866.1:c.1086GAG[1]`, `NM_001413867.1:c.1074GAG[1]`, `NM_001413868.1:c.1074GAG[1]`, `NM_001413869.1:c.1071GAG[1]`, `NM_001413870.1:c.1068GAG[1]`, `NM_001413871.1:c.1044GAG[1]`, `NM_001413872.1:c.1044GAG[1]`, `NM_001413873.1:c.1041GAG[1]`, `NM_001413874.1:c.1032GAG[1]`, `NM_001413875.1:c.1029GAG[1]`, `NM_001413876.1:c.1002GAG[1]`, `NM_001413877.1:c.1002GAG[1]`, `NM_001413878.1:c.999GAG[1]`, `NM_001413879.1:c.996GAG[1]`, `NM_001413880.1:c.987GAG[1]`, `NM_001413881.1:c.987GAG[1]`, `NM_001413882.1:c.984GAG[1]`, `NM_001413883.1:c.969GAG[1]`, `NM_001413884.1:c.966GAG[1]`, `NM_001413885.1:c.957GAG[1]`, `NM_001413886.1:c.945GAG[1]`, `NM_001413887.1:c.945GAG[1]`, `NM_001413888.1:c.942GAG[1]`, `NM_001413889.1:c.930GAG[1]`, `NM_001413890.1:c.924GAG[1]`, `NM_001413891.1:c.1173GAG[1]`, `NM_001413893.1:c.1170GAG[1]`, `NM_001413894.1:c.912GAG[1]`, `NM_001413895.1:c.867GAG[1]`, `NM_001413896.1:c.1116GAG[1]`, `NM_001413897.1:c.1044GAG[1]`, `NM_001413898.1:c.774GAG[1]`, `NM_001413899.1:c.1149+9480_1149+9482del`, `NM_001413900.1:c.687GAG[1]`, `NM_001413901.1:c.519GAG[1]`, `NM_001413909.1:c.561GAG[1]`, `NM_004318.4:c.1173GAG[1]`

## 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 -0.522, GERP -0.363, phastCons 0.027 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 16.65**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00769%** (sas) · FAF95 0.00359% · FAF99 0.00255% · 7/91,034 in the highest group · 21/1,613,556 alleles overall — very rare (popmax 0.00769%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00769% | 13,005 |
| East Asian | 0.00223% | 44,856 |
| European (non-Finnish) | 0.0011% | 90,758 |

*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}

**ASPH** population constraint: LOEUF 1.011, pLI 2.7445e-21, missense-Z -0.087304; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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}


AlphaFold model confidence (whole protein): pLDDT 72.34, 56% of residues very-high.

**43 experimental structure(s)** (PDB): [5APA](https://www.rcsb.org/structure/5APA), [5JQY](https://www.rcsb.org/structure/5JQY), [5JTC](https://www.rcsb.org/structure/5JTC), [5JZ6](https://www.rcsb.org/structure/5JZ6), [5JZ8](https://www.rcsb.org/structure/5JZ8), [5JZA](https://www.rcsb.org/structure/5JZA) — incl. mutant structure 8RE5.

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

*Describes the biological roles of ASPH (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:** ASPH's established molecular role includes calcium ion binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |
| [Protein hydroxylation](https://reactome.org/content/detail/R-HSA-9629569) | electronic |

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

**Molecular function:** calcium ion binding.

**Biological process:** positive regulation of calcium ion transport into cytosol, activation of store-operated calcium channel activity, response to ATP, positive regulation of proteolysis, positive regulation of DNA-templated transcription, phosphatidylinositol-mediated signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-07 |

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

## Similar variants {#similar}

Related ASPH variant pages (same residue, condition, or type): [ASPH c.322+4786GAA[7]](/variant/asph-c-322-plus-4786gaa-7), [ASPH c.322+4786GAA[5]](/variant/asph-c-322-plus-4786gaa-5).

### 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 3007500). 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.*