Is BTD p.Phe423Tyr (c.1268T>A) pathogenic?

BTD p.Phe423Tyr (c.1268T>A) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: likely benign (0.3324); Absent from gnomAD v4.1; Associated with biotinidase deficiency.

What condition is associated with BTD p.Phe423Tyr (c.1268T>A)?

BTD p.Phe423Tyr (c.1268T>A) is associated with biotinidase deficiency (ClinVar).

How common is BTD p.Phe423Tyr (c.1268T>A) in the general population?

BTD p.Phe423Tyr (c.1268T>A) is absent from gnomAD v4.1 (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.Phe423Tyr (c.1268T>A)?

AlphaMissense predicts likely benign (score 0.3324) — an in-silico prediction, not a clinical call.

BTD p.Phe423Tyr

c.1268T>A · rs1559600573 · VCV2159581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3324 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotinidase deficiency

Computational evidence

Protein change
AlphaMissense	0.3324	likely benign
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	26.2	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 F443Y vs ClinVar F423Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BTD
Protein: p.Phe423Tyr
Coding: c.1268T>A
MANE Select: NM_001370658
dbSNP: rs1559600573
Type: single nucleotide variant
Location: chr3:15645184 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77

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.Phe423Cys Uncertain significance ★ ⚠ 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-phe423tyr (accessed [today's date]).

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