# NM_182641.4(BPTF):c.1661A>T (p.Glu554Val)

https://sugi.bio/variant/bptf-p-glu554val

## Summary

**BPTF p.Glu554Val (c.1661A>T)** is classified **Uncertain significance** in BPTF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.7158); Very rare (popmax 0.00451%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs375245234 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00451%, nfe)

## 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 2 submitters, 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.Glu554Val |
| Coding change (HGVS c.) | c.1661A>T |
| MANE Select transcript | [NM_182641](https://www.ncbi.nlm.nih.gov/nuccore/NM_182641) |
| dbSNP | [rs375245234](https://www.ncbi.nlm.nih.gov/snp/rs375245234/) |
| Variant type | single nucleotide variant |
| Location | chr17:67874817-67874817 (GRCh38) |
| ClinVar | [VCV1699737](https://www.ncbi.nlm.nih.gov/clinvar/variation/1699737/) |

**All HGVS expressions:** `NC_000017.10:g.65870933A>T`, `NC_000017.11:g.67874817A>T`, `NG_052828.1:g.54301A>T`, `NM_004459.7:c.1661A>T`, `NM_182641.3:c.1661A>T`, `NM_182641.4:c.1661A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7158)
- REVEL 0.156 (moderately benign-leaning) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL does not
- SpliceAI predicts **acceptor gain** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.109, GERP 2.23, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.93** across the covering region of the MANE Select transcript (67,854,761–67,891,925), spanning 37,164 bp. Chi-square p 0.31. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**.
- Pangolin: Δ**0.27** (gain), gain 0.27 / loss 0.06. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00451%** (nfe) · FAF95 0.00352% · FAF99 0.00319% · 53/1,175,520 in the highest group · 60/1,602,516 alleles overall — very rare (popmax 0.00451%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00484% | 20,645 |
| European (non-Finnish) (grpmax) | 0.00451% | 22,180 |
| African / African-American | 0.00271% | 36,948 |
| Admixed American | 0.00174% | 57,386 |
| South Asian | 0.00112% | 89,130 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


**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.


### 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-20.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-25 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## 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 1699737). 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.*