# NM_001370658.1(BTD):c.1372G>C (p.Ala458Pro)

https://sugi.bio/variant/btd-p-ala458pro

## Summary

**BTD p.Ala458Pro (c.1372G>C)** is classified **Pathogenic/Likely pathogenic** in BTD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9137); Very rare (popmax 0.00878%, sas); Associated with biotinidase deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs181396238 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00878%, sas)

## For patients & families {#patients}

This is a change in the BTD gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to biotinidase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BTD is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Biotinidase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Organic aciduria — Very frequent (99-80%)
- Metabolic ketoacidosis — Very frequent (99-80%)
- Decreased biotinidase activity — Very frequent (99-80%)
- Sensorineural hearing impairment — Frequent (79-30%)
- Abnormality of the nervous system — Frequent (79-30%)
- Skin rash — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000894/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BTD](https://sugi.bio/atlas/gene/BTD/) |
| Protein change (HGVS p.) | p.Ala458Pro |
| Coding change (HGVS c.) | c.1372G>C |
| MANE Select transcript | [NM_001370658](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370658) |
| dbSNP | [rs181396238](https://www.ncbi.nlm.nih.gov/snp/rs181396238/) |
| Variant type | single nucleotide variant |
| Location | chr3:15645288-15645288 (GRCh38) |
| ClinVar | [VCV25089](https://www.ncbi.nlm.nih.gov/clinvar/variation/25089/) |

**All HGVS expressions:** `NC_000003.11:g.15686795G>C`, `NC_000003.12:g.15645288G>C`, `NG_008019.2:g.48937G>C`, `NG_008019.3:g.48938G>C`, `NM_000060.4:c.1432G>C`, `NM_001281723.4:c.1372G>C`, `NM_001281724.3:c.1372G>C`, `NM_001281725.3:c.1372G>C`, `NM_001323582.2:c.1372G>C`, `NM_001370658.1:c.1372G>C`, `NM_001370752.1:c.1015+357G>C`, `NM_001370753.1:c.399+3231G>C`, `NM_001407364.1:c.1372G>C`, `NM_001407365.1:c.1372G>C`, `NM_001407366.1:c.1372G>C`, `NM_001407367.1:c.1372G>C`, `NM_001407368.1:c.1372G>C`, `NM_001407369.1:c.1372G>C`, `NM_001407370.1:c.1372G>C`, `NM_001407371.1:c.1372G>C`, `NM_001407372.1:c.1372G>C`, `NM_001407373.1:c.1372G>C`, `NM_001407374.1:c.1372G>C`, `NM_001407375.1:c.1372G>C`, `NM_001407376.1:c.1372G>C`, `NM_001407377.1:c.1372G>C`, `NM_001407378.1:c.1372G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9137) — concordant with the pathogenic call
- REVEL 0.931 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.258 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 9.753, GERP 1.99, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A478P** vs ClinVar **A458P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in BTD (of 3,233 modeled).
- CADD: **PHRED 25.3**. 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 1.04** across the covering region of the MANE Select transcript (15,635,440–15,645,485), spanning 10,045 bp. Chi-square p 0.35. 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 **0.00878%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/91,082 in the highest group · 9/1,461,884 alleles overall — very rare (popmax 0.00878%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00878% | 11,385 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |

*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}

**BTD** population constraint: LOEUF 1.22, pLI 5.4385e-05, missense-Z 0.16275. *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):

- **Leigh syndrome** — Moderate (AR)
- **biotinidase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.77, 79% of residues very-high.

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

*Describes the biological roles of BTD (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:** BTD participates in disease-associated pathways. In Reactome, BTD is annotated in disease pathway(s) including **Defective BTD causes biotidinase deficiency**.

**Disease mechanism (Reactome):** BTD loss or alteration is curated in [Defective BTD causes biotidinase deficiency](https://reactome.org/content/detail/R-HSA-3371598).

### Pathways affected {#pathways}

BTD participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective BTD causes biotidinase deficiency](https://reactome.org/content/detail/R-HSA-3371598) | curated |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | curated |

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-07 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-03 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-02 |

## Associated conditions {#conditions}

[biotinidase deficiency](https://sugi.bio/atlas/disease/biotinidase-deficiency/).

**Reported phenotype names (ClinVar):** Biotinidase deficiency, not provided, none provided, BTD deficiency, Late-onset biotin-responsive multiple carboxylase deficiency, Biotin deficiency.

## Similar variants {#similar}

Related BTD variant pages (same residue, condition, or type): [BTD p.Ala458Thr](/variant/btd-p-ala458thr), [BTD c.1330G>C](/variant/btd-c-1330g-c), [BTD c.249+1G>T](/variant/btd-c-249-plus-1g-t), [BTD c.400-2A>G](/variant/btd-c-400-minus-2a-g), [BTD c.-17+2T>C](/variant/btd-c-minus-17-plus-2t-c), [BTD p.Ala142Val](/variant/btd-p-ala142val), [BTD p.Ala217Thr](/variant/btd-p-ala217thr), [BTD p.Ala269Val](/variant/btd-p-ala269val).

### 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 25089). 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.*