# NM_001370658.1(BTD):c.1429C>T (p.Pro477Ser)

https://sugi.bio/variant/btd-p-pro477ser

## Summary

**BTD p.Pro477Ser (c.1429C>T)** is classified **Pathogenic/Likely pathogenic** in BTD (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-01-20). AlphaMissense: ambiguous (0.4798); Ultra-rare (popmax 0.0573%, afr); Associated with BTD-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs138818907 · 17 submitters · 2 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0573%, afr)

## For patients & families {#patients}

This is a change in the BTD gene that is considered likely disease-causing, submitted by 17 submitters, and is linked to BTD-related disorder.

*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 | [BTD](https://sugi.bio/atlas/gene/BTD/) |
| Protein change (HGVS p.) | p.Pro477Ser |
| Coding change (HGVS c.) | c.1429C>T |
| MANE Select transcript | [NM_001370658](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370658) |
| dbSNP | [rs138818907](https://www.ncbi.nlm.nih.gov/snp/rs138818907/) |
| Variant type | single nucleotide variant |
| Location | chr3:15645345-15645345 (GRCh38) |
| ClinVar | [VCV25094](https://www.ncbi.nlm.nih.gov/clinvar/variation/25094/) |

**All HGVS expressions:** `NC_000003.11:g.15686852C>T`, `NC_000003.12:g.15645345C>T`, `NG_008019.2:g.48994C>T`, `NG_008019.3:g.48995C>T`, `NM_000060.4:c.1489C>T`, `NM_001281723.4:c.1429C>T`, `NM_001281724.3:c.1429C>T`, `NM_001281725.3:c.1429C>T`, `NM_001323582.2:c.1429C>T`, `NM_001370658.1:c.1429C>T`, `NM_001370752.1:c.1015+414C>T`, `NM_001370753.1:c.399+3288C>T`, `NM_001407364.1:c.1429C>T`, `NM_001407365.1:c.1429C>T`, `NM_001407366.1:c.1429C>T`, `NM_001407367.1:c.1429C>T`, `NM_001407368.1:c.1429C>T`, `NM_001407369.1:c.1429C>T`, `NM_001407370.1:c.1429C>T`, `NM_001407371.1:c.1429C>T`, `NM_001407372.1:c.1429C>T`, `NM_001407373.1:c.1429C>T`, `NM_001407374.1:c.1429C>T`, `NM_001407375.1:c.1429C>T`, `NM_001407376.1:c.1429C>T`, `NM_001407377.1:c.1429C>T`, `NM_001407378.1:c.1429C>T`, `NM_001407379.1:c.1015+414C>T`, `NM_001407380.1:c.399+3288C>T`, `NM_001407398.1:c.399+3288C>T`, `NM_001407399.1:c.399+3288C>T`, `NM_001407400.1:c.399+3288C>T`, `NM_001407401.1:c.399+3288C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4798) — no call either way
- REVEL 0.895 (moderately pathogenic-leaning)
- SaProt LLR -10.929 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 7.563, GERP 2.43, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P497S** vs ClinVar **P477S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.1**. 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 **0.0573%** (afr) · FAF95 0.0436% · FAF99 0.0389% · 43/75,046 in the highest group · 54/1,614,204 alleles overall — ultra-rare (popmax 0.0573%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0573% | 1,745 |
| Middle Eastern | 0.0165% | 6,062 |
| Admixed American | 0.00167% | 60,032 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000593% | 168,576 |

*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 2026-01-20.

**Submitter consensus:** conflicting (15 Pathogenic, 2 Likely pathogenic).

**Submission history:** 17 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2017-11-27 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2012-09-10 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | research | 2024-03-17 |
| Dubai Health Genomic Medicine Center, Dubai Health | Pathogenic | criteria provided, single submitter | research | 2024-10-04 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-22 |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-05-09 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-10 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-15 |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-02 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-15 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-12-21 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-20 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-19 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-01 |

## Associated conditions {#conditions}

[BTD-related disorder](https://sugi.bio/atlas/disease/btd-related-disorder/), [biotinidase deficiency](https://sugi.bio/atlas/disease/biotinidase-deficiency/).

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

## Same-residue context {#hotspot}

Residue **477** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BTD p.Pro477Leu](/variant/btd-p-pro477leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BTD variant pages (same residue, condition, or type): [BTD p.Pro477Leu](/variant/btd-p-pro477leu), [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 2026-10-14); 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 25094). 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.*