# NM_182641.4(BPTF):c.202del (p.Arg68fs)

https://sugi.bio/variant/bptf-p-arg68fs

## Summary

**BPTF p.Arg68fs (c.202del)** is classified **Pathogenic** in BPTF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the BPTF gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [BPTF](https://sugi.bio/atlas/gene/BPTF/) |
| Protein change (HGVS p.) | p.Arg68fs |
| Coding change (HGVS c.) | c.202del |
| MANE Select transcript | [NM_182641](https://www.ncbi.nlm.nih.gov/nuccore/NM_182641) |
| Variant type | Deletion |
| Location | chr17:67825926-67825926 (GRCh38) |
| ClinVar | [VCV4214990](https://www.ncbi.nlm.nih.gov/clinvar/variation/4214990/) |

**All HGVS expressions:** `NC_000017.10:g.65822042del`, `NC_000017.11:g.67825926del`, `NG_052828.1:g.5410del`, `NG_137337.1:g.578del`, `NM_001439139.1:c.202del`, `NM_001439140.1:c.202del`, `NM_001439141.1:c.202del`, `NM_001439142.1:c.202del`, `NM_001439143.1:c.202del`, `NM_001439144.1:c.202del`, `NM_004459.7:c.202del`, `NM_182641.4:c.202del`

## 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 2.129, GERP -0.547, phastCons 0.993 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.09, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 28**, 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.
- Repeat context: **segmental_duplication** (chr17:68203655, chr17:45564079). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*

*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}

**BPTF** population constraint: LOEUF 0.09, pLI 1, missense-Z 5.0945; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **68** lies in the 'disordered' region.

**46 experimental structure(s)** (PDB): [2F6J](https://www.rcsb.org/structure/2F6J), [2F6N](https://www.rcsb.org/structure/2F6N), [2FSA](https://www.rcsb.org/structure/2FSA), [2FUI](https://www.rcsb.org/structure/2FUI), [2FUU](https://www.rcsb.org/structure/2FUU), [2RI7](https://www.rcsb.org/structure/2RI7) — incl. mutant structure 2RI7.

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

*Describes the biological roles of BPTF (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:** BPTF's established molecular role includes sequence-specific DNA binding. p.Arg68fs falls in the disordered region.


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

**Molecular function:** sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, brain development, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-11.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related BPTF variant pages (same residue, condition, or type): [BPTF p.Arg68Ser](/variant/bptf-p-arg68ser), [BPTF p.Arg68Met](/variant/bptf-p-arg68met), [BPTF p.Arg68Thr](/variant/bptf-p-arg68thr), [BPTF p.Asn789fs](/variant/bptf-p-asn789fs), [BPTF p.Arg101_Gly105del](/variant/bptf-p-arg101-gly105del), [BPTF p.Thr1631del](/variant/bptf-p-thr1631del), [BPTF p.Thr783fs](/variant/bptf-p-thr783fs), [BPTF p.Ala1197Val](/variant/bptf-p-ala1197val).

### 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 4214990). 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.*