Is BTD p.Phe129Leu (c.385T>C) pathogenic?

BTD p.Phe129Leu (c.385T>C) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.9357); Very rare (popmax 0.000169%, nfe); Associated with biotinidase deficiency.

What condition is associated with BTD p.Phe129Leu (c.385T>C)?

BTD p.Phe129Leu (c.385T>C) is associated with biotinidase deficiency (ClinVar).

How common is BTD p.Phe129Leu (c.385T>C) in the general population?

BTD p.Phe129Leu (c.385T>C) is very rare (popmax 0.000169%, 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.Phe129Leu (c.385T>C)?

AlphaMissense predicts likely pathogenic (score 0.9357) — an in-silico prediction, not a clinical call.

BTD p.Phe129Leu

c.385T>C · rs397514359 · VCV25007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9357 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotinidase deficiency

Computational evidence

Protein change
AlphaMissense	0.9357	likely pathogenic · top 6% in BTD
REVEL	0.749	pathogenic-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	25.7	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 F149L vs ClinVar F129L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,032 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,058 alleles · very rare

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.Phe129Leu
Coding: c.385T>C
MANE Select: NM_001370658
dbSNP: rs397514359
Type: single nucleotide variant
Location: chr3:15642043 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 129: 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 p.Phe129= Likely benign ★ same residue
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

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-phe129leu (accessed [today's date]).

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