Is BTD p.Pro53Leu (c.158C>T) pathogenic?

BTD p.Pro53Leu (c.158C>T) is classified Pathogenic in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely benign (0.3212); Very rare (popmax 8.47e-05%, nfe); Associated with biotinidase deficiency.

What condition is associated with BTD p.Pro53Leu (c.158C>T)?

BTD p.Pro53Leu (c.158C>T) is associated with biotinidase deficiency (ClinVar).

How common is BTD p.Pro53Leu (c.158C>T) in the general population?

BTD p.Pro53Leu (c.158C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Biotinidase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BTD p.Pro53Leu (c.158C>T)?

AlphaMissense predicts likely benign (score 0.3212) — an in-silico prediction, not a clinical call.

BTD p.Pro53Leu

c.158C>T · VCV4707435

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotinidase deficiency

Computational evidence

Protein change
AlphaMissense	0.3212	likely benign ⚠ discordant with ClinVar
REVEL	0.743	pathogenic-leaning
SaProt	LLR -10.59	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.46, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P73L vs ClinVar P53L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,054 alleles

Overall 0.000124% 2/1,614,114 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)grpmax	8.47e-05%	1,180,054

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BTD
Protein: p.Pro53Leu
Coding: c.158C>T
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15635597 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 53: the cn hydrolase domain

Full BTD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

biotinidase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Biotinidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

BTD c.1330G>C Pathogenic ★★ same condition
BTD c.249+1G>T Likely pathogenic ★★ same condition
BTD c.400-2A>G Likely pathogenic ★★ same condition
BTD c.-17+2T>C Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala142Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala217Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
BTD p.Ala269Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala279Pro Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/btd-p-pro53leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown