# NM_182641.4(BPTF):c.2044G>A (p.Glu682Lys)

https://sugi.bio/variant/bptf-p-glu682lys

## Summary

**BPTF p.Glu682Lys (c.2044G>A)** is classified **Uncertain significance** in BPTF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely pathogenic (0.7122); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BPTF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Glu682Lys |
| Coding change (HGVS c.) | c.2044G>A |
| MANE Select transcript | [NM_182641](https://www.ncbi.nlm.nih.gov/nuccore/NM_182641) |
| Variant type | single nucleotide variant |
| Location | chr17:67892023-67892023 (GRCh38) |
| ClinVar | [VCV4598604](https://www.ncbi.nlm.nih.gov/clinvar/variation/4598604/) |

**All HGVS expressions:** `NC_000017.10:g.65888139G>A`, `NC_000017.11:g.67892023G>A`, `NG_052828.1:g.71507G>A`, `NM_001439139.1:c.2233G>A`, `NM_001439140.1:c.2422G>A`, `NM_001439141.1:c.2233G>A`, `NM_001439142.1:c.2422G>A`, `NM_001439143.1:c.2233G>A`, `NM_001439144.1:c.2233G>A`, `NM_004459.7:c.2422G>A`, `NM_182641.4:c.2044G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7122)
- REVEL 0.287 (benign-leaning) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL does not
- Conservation: phyloP 11.708, GERP 6, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **E808K** vs ClinVar **E682K**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.6**. 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 0.75** across the covering region of the MANE Select transcript (67,891,982–67,893,529), spanning 1,547 bp. Chi-square p 0.022. 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 (G>T, Δ0.34 donor gain), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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, triplosensitivity 0 (0–3 scale). *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 **682** lies in the 'disordered' region; the 'interaction with keap1' 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.Glu682Lys 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-18 |

## 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.Ala1197Val](/variant/bptf-p-ala1197val), [BPTF p.Ala1252Val](/variant/bptf-p-ala1252val), [BPTF p.Arg1078Gln](/variant/bptf-p-arg1078gln), [BPTF p.Arg2139His](/variant/bptf-p-arg2139his), [BPTF p.Arg215His](/variant/bptf-p-arg215his), [BPTF p.Arg2352His](/variant/bptf-p-arg2352his), [BPTF p.Arg2858Gln](/variant/bptf-p-arg2858gln), [BPTF p.Arg68Ser](/variant/bptf-p-arg68ser).

### 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 4598604). 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.*