# NM_014680.5(BLTP2):c.748A>G (p.Lys250Glu)

https://sugi.bio/variant/bltp2-p-lys250glu

## Summary

**BLTP2 p.Lys250Glu (c.748A>G)** is classified **Uncertain significance** in BLTP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the BLTP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [BLTP2](https://sugi.bio/atlas/gene/BLTP2/) |
| Protein change (HGVS p.) | p.Lys250Glu |
| Coding change (HGVS c.) | c.748A>G |
| MANE Select transcript | [NM_014680](https://www.ncbi.nlm.nih.gov/nuccore/NM_014680) |
| Variant type | single nucleotide variant |
| Location | chr17:28641907-28641907 (GRCh38) |
| ClinVar | [VCV4646082](https://www.ncbi.nlm.nih.gov/clinvar/variation/4646082/) |

**All HGVS expressions:** `NC_000017.10:g.26968925T>C`, `NC_000017.11:g.28641907T>C`, `NG_053109.1:g.8548A>G`, `NM_001321560.2:c.748A>G`, `NM_001321561.2:c.748A>G`, `NM_001363826.1:c.319A>G`, `NM_001363827.1:c.-272A>G`, `NM_001363828.1:c.-1072A>G`, `NM_001363829.1:c.-1446A>G`, `NM_014680.5:c.748A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0881)
- REVEL 0.048 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.54 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.065, GERP 0.606, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.34**. 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 0.98** across the covering region of the MANE Select transcript (28,634,874–28,645,056), spanning 10,182 bp. Chi-square p 0.6. 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 (T>A, 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 **0.0011%** (sas) · 1/91,068 in the highest group · 1/1,460,914 alleles overall — very rare (popmax 0.0011%, sas).

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.37, 11% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-25.

**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 | 2025-09-25 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BLTP2 variant pages (same residue, condition, or type): [BLTP2 p.Lys250Asn](/variant/bltp2-p-lys250asn), [BLTP2 p.Ala1395Ser](/variant/bltp2-p-ala1395ser), [BLTP2 p.Ala1564Thr](/variant/bltp2-p-ala1564thr), [BLTP2 p.Ala1826Thr](/variant/bltp2-p-ala1826thr), [BLTP2 p.Ala248Thr](/variant/bltp2-p-ala248thr), [BLTP2 p.Ala324Thr](/variant/bltp2-p-ala324thr), [BLTP2 p.Ala393Thr](/variant/bltp2-p-ala393thr), [BLTP2 p.Ala539Thr](/variant/bltp2-p-ala539thr).

### 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 4646082). 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.*