# NM_001195248.2(APTX):c.596del (p.Arg199fs)

https://sugi.bio/variant/aptx-p-arg199fs

## Summary

**APTX p.Arg199fs (c.596del)** is classified **Pathogenic/Likely pathogenic** in APTX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-11). Very rare (popmax 0.00659%, sas); Associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs770007531 · 4 submitters · 1 linked condition · very rare (popmax 0.00659%, sas)

## For patients & families {#patients}

This is a change in the APTX gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia.

*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 | APTX is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Ataxia-oculomotor apraxia type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Ataxia — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Peripheral neuropathy — Very frequent (99-80%)
- Medial flaring of the eyebrow — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009283/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [APTX](https://sugi.bio/atlas/gene/APTX/) |
| Protein change (HGVS p.) | p.Arg199fs |
| Coding change (HGVS c.) | c.596del |
| MANE Select transcript | [NM_001195248](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195248) |
| dbSNP | [rs770007531](https://www.ncbi.nlm.nih.gov/snp/rs770007531/) |
| Variant type | Deletion |
| Location | chr9:32984805-32984805 (GRCh38) |
| ClinVar | [VCV1323370](https://www.ncbi.nlm.nih.gov/clinvar/variation/1323370/) |

**All HGVS expressions:** `NC_000009.11:g.32984803del`, `NC_000009.12:g.32984805del`, `NG_012821.2:g.45327del`, `NM_001195248.2:c.596del`, `NM_001195249.2:c.596del`, `NM_001195250.2:c.434del`, `NM_001195251.2:c.596del`, `NM_001195252.2:c.380del`, `NM_001195254.2:c.434del`, `NM_001368995.1:c.596del`, `NM_001368996.1:c.596del`, `NM_001368997.1:c.596del`, `NM_001368998.1:c.596del`, `NM_001368999.1:c.596del`, `NM_001369000.1:c.434del`, `NM_001369001.1:c.434del`, `NM_001369002.1:c.332del`, `NM_001369003.1:c.332del`, `NM_001369004.1:c.332del`, `NM_001369005.1:c.332del`, `NM_001369006.1:c.332del`, `NM_001370669.1:c.332del`, `NM_001370670.1:c.332del`, `NM_001370673.1:c.332del`, `NM_175069.3:c.596del`, `NM_175069.3:c.596delG`, `NM_175073.3:c.596del`, `NR_036577.2:n.547del`, `NR_160921.1:n.566del`, `NR_160922.1:n.797del`, `NR_160923.1:n.601del`, `NR_160924.1:n.606del`, `NR_160925.1:n.802del`, `NR_160926.1:n.592del`, `NR_160930.1:n.542del`, `NR_160931.1:n.781del`

## 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 1.681, GERP 0.457, phastCons 0.846 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.973, pLI 2.0655e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 8**, so the transcript is predicted to undergo NMD.
- 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 **0.00659%** (sas) · FAF95 0.00286% · FAF99 0.00195% · 6/91,084 in the highest group · 7/1,614,212 alleles overall — very rare (popmax 0.00659%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00659% | 15,181 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,512 |

*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}

**APTX** population constraint: LOEUF 0.973, pLI 2.0655e-07, missense-Z 0.27421. *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 **199** lies in the hit domain.

AlphaFold model confidence (whole protein): pLDDT 81.52, 64% of residues very-high.

**11 experimental structure(s)** (PDB): [3KT9](https://www.rcsb.org/structure/3KT9), [4NDF](https://www.rcsb.org/structure/4NDF), [4NDG](https://www.rcsb.org/structure/4NDG), [4NDH](https://www.rcsb.org/structure/4NDH), [4NDI](https://www.rcsb.org/structure/4NDI), [6CVO](https://www.rcsb.org/structure/6CVO) — incl. mutant structure 4NDI.

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

*Describes the biological roles of APTX (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:** APTX's established molecular role includes chromatin binding. p.Arg199fs falls in the hit domain.


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

**Molecular function:** chromatin binding, damaged DNA binding, double-stranded DNA binding, double-stranded RNA binding, phosphoglycolate phosphatase activity, DNA 5'-adenosine monophosphate hydrolase activity.

**Biological process:** single strand break repair, regulation of protein stability.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-11.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lifecell International Pvt. Ltd | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Likely pathogenic | criteria provided, single submitter | research | 2025-12-11 |

## Associated conditions {#conditions}

[ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia](https://sugi.bio/atlas/disease/ataxia-early-onset-with-oculomotor-apraxia-and-hypoalbuminemia/).

**Reported phenotype names (ClinVar):** Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia, ATAXIA-OCULOMOTOR APRAXIA SYNDROME, ATAXIA-TELANGIECTASIA-LIKE SYNDROME, Ataxia-oculomotor apraxia type 1.

## Similar variants {#similar}

Related APTX variant pages (same residue, condition, or type): [APTX p.Arg199His](/variant/aptx-p-arg199his), [APTX p.Val259fs](/variant/aptx-p-val259fs), [APTX p.Arg199Cys](/variant/aptx-p-arg199cys), [APTX c.484-25_484-4del](/variant/aptx-c-484-minus-25-484-minus-4del), [APTX c.484-25_484-5del](/variant/aptx-c-484-minus-25-484-minus-5del), [APTX c.484-25_484-6del](/variant/aptx-c-484-minus-25-484-minus-6del), [APTX c.874+1del](/variant/aptx-c-874-plus-1del), [APTX p.Leu213fs](/variant/aptx-p-leu213fs).

### 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 1323370). 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.*