# NM_025233.7(COASY):c.864C>T (p.Ser288=)

https://sugi.bio/variant/coasy-p-ser288

## Summary

**COASY p.Ser288= (c.864C>T)** is classified **Uncertain significance** in COASY (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-02). Very rare (popmax 0.00833%, amr); Associated with neurodegeneration with brain iron accumulation 6.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370902320 · 2 submitters · 1 linked condition · very rare (popmax 0.00833%, amr)

## For patients & families {#patients}

This is a change in the COASY gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to neurodegeneration with brain iron accumulation 6.

*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) | Childhood |
| Diagnostic panels | COASY is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of COASY protein-associated neurodegeneration** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Compulsive behaviors — Very frequent (99-80%)
- Dysarthria — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Parkinsonism — Very frequent (99-80%)
- Spastic paraparesis — Very frequent (99-80%)
- Abnormal caudate nucleus morphology — Very frequent (99-80%)
- Abnormal globus pallidus morphology — Very frequent (99-80%)
- Eye of the tiger anomaly of globus pallidus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012571/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COASY](https://sugi.bio/atlas/gene/COASY/) |
| Protein change (HGVS p.) | p.Ser288= |
| Coding change (HGVS c.) | c.864C>T |
| MANE Select transcript | [NM_025233](https://www.ncbi.nlm.nih.gov/nuccore/NM_025233) |
| dbSNP | [rs370902320](https://www.ncbi.nlm.nih.gov/snp/rs370902320/) |
| Variant type | single nucleotide variant |
| Location | chr17:42564124-42564124 (GRCh38) |
| ClinVar | [VCV2059681](https://www.ncbi.nlm.nih.gov/clinvar/variation/2059681/) |

**All HGVS expressions:** `NC_000017.10:g.40716142C>T`, `NC_000017.11:g.42564124C>T`, `NG_029442.1:g.2065C>T`, `NG_034110.1:g.7051C>T`, `NM_001042529.3:c.864C>T`, `NM_001042532.4:c.951C>T`, `NM_025233.7:c.864C>T`

## 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 gain** (Δ 0.64) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.054, GERP 2.77, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.2**. 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 **0.00**, acceptor gain **0.00**, donor gain **0.64**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.64**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.00. 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 **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,998 in the highest group · 30/1,613,956 alleles overall — very rare (popmax 0.00833%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00833% | 12,000 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| European (non-Finnish) | 0.00195% | 51,305 |

*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}

**COASY** population constraint: LOEUF 0.791, pLI 2.6657e-06, missense-Z 0.27059. *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 **288** lies in a UniProt-annotated variant site (in nbia6; reduced protein abundance); the 'phosphopantetheine adenylyltransferase domain' region.

AlphaFold model confidence (whole protein): pLDDT 89.51, 74% of residues very-high.

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

*Describes the biological roles of COASY (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:** COASY's established molecular role includes dephospho-CoA kinase activity. p.Ser288= falls in the phosphopantetheine adenylyltransferase domain region.


### Pathways affected {#pathways}

COASY participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Coenzyme A biosynthesis](https://reactome.org/content/detail/R-HSA-196783) | curated |

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

**Molecular function:** dephospho-CoA kinase activity, pantetheine-phosphate adenylyltransferase activity.

**Biological process:** coenzyme A biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-02.

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

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-02 |

## Associated conditions {#conditions}

[neurodegeneration with brain iron accumulation 6](https://sugi.bio/atlas/disease/neurodegeneration-with-brain-iron-accumulation-6/).

**Reported phenotype names (ClinVar):** Neurodegeneration with brain iron accumulation 6, Gastric cancer, COASY protein-associated neurodegeneration.

## Similar variants {#similar}

Related COASY variant pages (same residue, condition, or type): [COASY c.1486-3C>G](/variant/coasy-c-1486-minus-3c-g), [COASY p.Ala214Val](/variant/coasy-p-ala214val), [COASY p.Arg377Ter](/variant/coasy-p-arg377ter), [COASY p.Arg499Cys](/variant/coasy-p-arg499cys), [COASY p.Gln523Ter](/variant/coasy-p-gln523ter), [COASY p.Ala206Ser](/variant/coasy-p-ala206ser), [COASY p.Ala311Val](/variant/coasy-p-ala311val), [COASY p.Ala395Thr](/variant/coasy-p-ala395thr).

### 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 2059681). 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.*