# NM_001195248.2(APTX):c.617C>T (p.Pro206Leu)

https://sugi.bio/variant/aptx-p-pro206leu

## Summary

**APTX p.Pro206Leu (c.617C>T)** is classified **Pathogenic** in APTX (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-13). Ultra-rare (popmax 0.0164%, mid); Associated with APTX-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs121908131 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the APTX gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to APTX-related disorder.

*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 | [APTX](https://sugi.bio/atlas/gene/APTX/) |
| Protein change (HGVS p.) | p.Pro206Leu |
| Coding change (HGVS c.) | c.617C>T |
| MANE Select transcript | [NM_001195248](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195248) |
| dbSNP | [rs121908131](https://www.ncbi.nlm.nih.gov/snp/rs121908131/) |
| Variant type | single nucleotide variant |
| Location | chr9:32984784-32984784 (GRCh38) |
| ClinVar | [VCV4426](https://www.ncbi.nlm.nih.gov/clinvar/variation/4426/) |

**All HGVS expressions:** `NC_000009.11:g.32984782G>A`, `NC_000009.12:g.32984784G>A`, `NG_012821.2:g.45348C>T`, `NM_001195248.2:c.617C>T`, `NM_001195249.2:c.617C>T`, `NM_001195250.2:c.455C>T`, `NM_001195251.2:c.617C>T`, `NM_001195252.2:c.401C>T`, `NM_001195254.2:c.455C>T`, `NM_001368995.1:c.617C>T`, `NM_001368996.1:c.617C>T`, `NM_001368997.1:c.617C>T`, `NM_001368998.1:c.617C>T`, `NM_001368999.1:c.617C>T`, `NM_001369000.1:c.455C>T`, `NM_001369001.1:c.455C>T`, `NM_001369002.1:c.353C>T`, `NM_001369003.1:c.353C>T`, `NM_001369004.1:c.353C>T`, `NM_001369005.1:c.353C>T`, `NM_001369006.1:c.353C>T`, `NM_001370669.1:c.353C>T`, `NM_001370670.1:c.353C>T`, `NM_001370673.1:c.353C>T`, `NM_175069.3:c.617C>T`, `NM_175073.3:c.617C>T`, `NR_036577.2:n.568C>T`, `NR_160921.1:n.587C>T`, `NR_160922.1:n.818C>T`, `NR_160923.1:n.622C>T`, `NR_160924.1:n.627C>T`, `NR_160925.1:n.823C>T`, `NR_160926.1:n.613C>T`, `NR_160930.1:n.563C>T`, `NR_160931.1:n.802C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.746, GERP 1.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 32.0**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00177% · FAF99 0.000891% · 1/6,084 in the highest group · 16/1,614,054 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| East Asian | 0.00668% | 14,967 |
| South Asian | 0.0011% | 91,088 |
| European (non-Finnish) | 0.000932% | 107,276 |

*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 **206** lies in the hit domain; a β-strand.

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.Pro206Leu 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-13.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2001–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2001-10-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-13 |

## Associated conditions {#conditions}

[APTX-related disorder](https://sugi.bio/atlas/disease/aptx-related-disorder/), [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):** APTX-related disorder, Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia, APTX-related condition, 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.Pro206=](/variant/aptx-p-pro206), [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.Arg247Ter](/variant/aptx-p-arg247ter), [APTX p.Gln130Ter](/variant/aptx-p-gln130ter), [APTX p.Trp279Ter](/variant/aptx-p-trp279ter), [APTX p.Arg247Gln](/variant/aptx-p-arg247gln).

### 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 4426). 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.*