# NM_001750.7(CAST):c.1011G>A (p.Glu337=)

https://sugi.bio/variant/cast-p-glu337

## Summary

**CAST p.Glu337= (c.1011G>A)** is classified **Uncertain significance** in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). Ultra-rare (popmax 0.0701%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs774410415 · 1 submitter · ultra-rare (popmax 0.0701%, amr)

## For patients & families {#patients}

This is a change in the CAST 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 | [CAST](https://sugi.bio/atlas/gene/CAST/) |
| Protein change (HGVS p.) | p.Glu337= |
| Coding change (HGVS c.) | c.1011G>A |
| dbSNP | [rs774410415](https://www.ncbi.nlm.nih.gov/snp/rs774410415/) |
| Variant type | single nucleotide variant |
| Location | chr5:96741358-96741358 (GRCh38) |
| ClinVar | [VCV2905661](https://www.ncbi.nlm.nih.gov/clinvar/variation/2905661/) |

**All HGVS expressions:** `NC_000005.10:g.96741358G>A`, `NC_000005.9:g.96077062G>A`, `NG_029490.2:g.84322G>A`, `NM_001042440.5:c.888G>A`, `NM_001042441.3:c.954G>A`, `NM_001042442.3:c.945G>A`, `NM_001042443.3:c.762G>A`, `NM_001042444.3:c.639G>A`, `NM_001042445.3:c.657G>A`, `NM_001042446.3:c.600G>A`, `NM_001190442.2:c.723G>A`, `NM_001284212.4:c.639G>A`, `NM_001284213.4:c.546G>A`, `NM_001329966.1:c.945G>A`, `NM_001330626.2:c.915G>A`, `NM_001330627.2:c.888G>A`, `NM_001330628.2:c.843G>A`, `NM_001330629.2:c.927G>A`, `NM_001330630.2:c.600G>A`, `NM_001330631.2:c.723G>A`, `NM_001330632.2:c.696G>A`, `NM_001330633.2:c.705G>A`, `NM_001330634.2:c.666G>A`, `NM_001375317.1:c.900G>A`, `NM_001423250.1:c.762G>A`, `NM_001423251.1:c.723G>A`, `NM_001423252.1:c.723G>A`, `NM_001423253.1:c.696G>A`, `NM_001423254.1:c.696G>A`, `NM_001423255.1:c.657G>A`, `NM_001423256.1:c.657G>A`, `NM_001423257.1:c.657G>A`, `NM_001423258.1:c.657G>A`, `NM_001423259.1:c.657G>A`, `NM_001423260.1:c.600G>A`, `NM_001750.7:c.1011G>A`, `NM_173060.5:c.696G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.75) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.883, GERP 2.72, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 24.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.75**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.75**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.80** (loss), gain 0.00 / loss 0.80. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0701%** (amr) · FAF95 0.0533% · FAF99 0.0474% · 42/59,954 in the highest group · 45/1,599,956 alleles overall — ultra-rare (popmax 0.0701%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0701% | 1,427 |
| Remaining individuals (not grpmax-eligible) | 0.00323% | 30,992 |
| European (non-Finnish) | 8.57e-05% | 1,167,406 |

*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}

**CAST** population constraint: LOEUF 1.208, pLI 6.0475e-05, missense-Z -0.46104. *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 **337** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.67, 6% of residues very-high.

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

*Describes the biological roles of CAST (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:** CAST's established molecular role includes RNA binding. p.Glu337= falls in the disordered region. In Reactome, CAST is annotated in disease pathway(s) including **Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models**.

**Disease mechanism (Reactome):** CAST loss or alteration is curated in [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803).

### Pathways affected {#pathways}

CAST participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803) | electronic |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |

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

**Molecular function:** RNA binding, calcium-dependent cysteine-type endopeptidase inhibitor activity, cadherin binding.

**Biological process:** presynaptic active zone organization, negative regulation of type B pancreatic cell apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-12.

**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 | 2023-09-12 |

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

## Similar variants {#similar}

Related CAST variant pages (same residue, condition, or type): [PCSK1 p.Lys286Ter](/variant/pcsk1-p-lys286ter), [CAST p.Ala329Gly](/variant/cast-p-ala329gly), [CAST p.Asp160Val](/variant/cast-p-asp160val), [CAST p.Gln731His](/variant/cast-p-gln731his), [CAST p.Glu296Gly](/variant/cast-p-glu296gly), [CAST p.Ile274Val](/variant/cast-p-ile274val), [CAST p.Leu586Pro](/variant/cast-p-leu586pro), [CAST p.Ser231Leu](/variant/cast-p-ser231leu).

### 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 2905661). 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.*