Is BTD p.Cys451= (c.1353T>C) pathogenic?

BTD p.Cys451= (c.1353T>C) is classified Benign in BTD (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 33.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with biotinidase deficiency.

What condition is associated with BTD p.Cys451= (c.1353T>C)?

BTD p.Cys451= (c.1353T>C) is associated with biotinidase deficiency (ClinVar).

How is Biotinidase deficiency inherited?

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

BTD p.Cys451=

Q: How common is BTD p.Cys451= (c.1353T>C) in the general population?

BTD p.Cys451= (c.1353T>C) is common (popmax 33.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1353T>C · rs3817641 · VCV25088

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 33.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

biotinidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -4.3
Overall
CADD	1.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 33.5% East Asian · 15,054/44,874 alleles

Filtering AF 33.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.9%

Overall 9.85% 158,951/1,614,080 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	33.5%	3
Admixed American	15.5%	6
South Asian	14.5%	7
Remaining individualsnot grpmax-eligible	10.6%	9
European (non-Finnish)	8.67%	12
Finnishnot grpmax-eligible	8.67%	12
African / African-American	6.83%	15
Amishnot grpmax-eligible	5.37%	19
Middle Eastern	5.3%	19
Ashkenazi Jewishnot grpmax-eligible	4.85%	21

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.Cys451=
Coding: c.1353T>C
MANE Select: NM_001370658
dbSNP: rs3817641
Type: single nucleotide variant
Location: chr3:15645269 (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.Cys451Phe Likely pathogenic ★ same residue
BTD p.Cys451Ser Uncertain significance ★ ⚠ same residue
BTD p.Cys451fs Pathogenic ★★ 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

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-cys451 (accessed [today's date]).

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