# NM_001195248.2(APTX):c.740G>A (p.Arg247Gln)

https://sugi.bio/variant/aptx-p-arg247gln

## Summary

**APTX p.Arg247Gln (c.740G>A)** is classified **Uncertain significance** in APTX (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-20). Ultra-rare (popmax 0.0493%, mid); Associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs142133683 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0493%, mid)

## For patients & families {#patients}

This is a change in the APTX gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 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.Arg247Gln |
| Coding change (HGVS c.) | c.740G>A |
| MANE Select transcript | [NM_001195248](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195248) |
| dbSNP | [rs142133683](https://www.ncbi.nlm.nih.gov/snp/rs142133683/) |
| Variant type | single nucleotide variant |
| Location | chr9:32984661-32984661 (GRCh38) |
| ClinVar | [VCV366591](https://www.ncbi.nlm.nih.gov/clinvar/variation/366591/) |

**All HGVS expressions:** `NC_000009.11:g.32984659C>T`, `NC_000009.12:g.32984661C>T`, `NG_012821.2:g.45471G>A`, `NM_001195248.2:c.740G>A`, `NM_001195249.2:c.740G>A`, `NM_001195250.2:c.578G>A`, `NM_001195251.2:c.740G>A`, `NM_001195252.2:c.524G>A`, `NM_001195254.2:c.578G>A`, `NM_001368995.1:c.740G>A`, `NM_001368996.1:c.740G>A`, `NM_001368997.1:c.740G>A`, `NM_001368998.1:c.740G>A`, `NM_001368999.1:c.740G>A`, `NM_001369000.1:c.578G>A`, `NM_001369001.1:c.578G>A`, `NM_001369002.1:c.476G>A`, `NM_001369003.1:c.476G>A`, `NM_001369004.1:c.476G>A`, `NM_001369005.1:c.476G>A`, `NM_001369006.1:c.476G>A`, `NM_001370669.1:c.476G>A`, `NM_001370670.1:c.476G>A`, `NM_001370673.1:c.476G>A`, `NM_175069.3:c.740G>A`, `NM_175073.3:c.740G>A`, `NR_036577.2:n.691G>A`, `NR_160921.1:n.710G>A`, `NR_160922.1:n.941G>A`, `NR_160923.1:n.745G>A`, `NR_160924.1:n.750G>A`, `NR_160925.1:n.946G>A`, `NR_160926.1:n.736G>A`, `NR_160930.1:n.686G>A`, `NR_160931.1:n.925G>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 (below), not from a missing predictor score.
- Conservation: phyloP 7.618, GERP 1.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.6**. 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.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (32,973,501–32,989,891), spanning 16,390 bp. Chi-square p 0.77. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.20 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0493%** (mid) · FAF95 0.0134% · FAF99 0.00715% · 3/6,084 in the highest group · 78/1,614,064 alleles overall — ultra-rare (popmax 0.0493%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0493% | 2,028 |
| European (non-Finnish) | 0.00593% | 16,858 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| African / African-American | 0.00267% | 37,459 |
| Admixed American | 0.00167% | 60,002 |

*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 **247** lies in the hit domain; an α-helix.

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.Arg247Gln 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-20.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2016–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-06 |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-12 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-06-01 |

## 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, not provided, none provided, Ataxia-oculomotor apraxia type 1, ATAXIA-OCULOMOTOR APRAXIA SYNDROME, ATAXIA-TELANGIECTASIA-LIKE SYNDROME.

## Same-residue context {#hotspot}

Residue **247** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [APTX p.Arg247Ter](/variant/aptx-p-arg247ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APTX variant pages (same residue, condition, or type): [APTX p.Arg247Ter](/variant/aptx-p-arg247ter), [APTX c.875-2A>G](/variant/aptx-c-875-minus-2a-g), [APTX p.Ala198Val](/variant/aptx-p-ala198val), [APTX p.Arg16Ter](/variant/aptx-p-arg16ter), [APTX p.Gln130Ter](/variant/aptx-p-gln130ter), [APTX p.Trp279Ter](/variant/aptx-p-trp279ter), [APTX p.Glu125Asp](/variant/aptx-p-glu125asp), [APTX p.His166Tyr](/variant/aptx-p-his166tyr).

### 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 366591). 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.*