Is BTD p.Ser291fs (c.873del) pathogenic?

BTD p.Ser291fs (c.873del) is classified Pathogenic/Likely pathogenic in BTD (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-12-21). Very rare (popmax 0.00237%, nfe); Associated with biotinidase deficiency.

What condition is associated with BTD p.Ser291fs (c.873del)?

BTD p.Ser291fs (c.873del) is associated with biotinidase deficiency (ClinVar).

How common is BTD p.Ser291fs (c.873del) in the general population?

BTD p.Ser291fs (c.873del) is very rare (popmax 0.00237%, nfe) (gnomAD).

How is Biotinidase deficiency inherited?

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

BTD p.Ser291fs

c.873del · rs397514395 · VCV25052

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

biotinidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,048 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00192% 31/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,145
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,890

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.Ser291fs
Coding: c.873del
MANE Select: NM_001370658
dbSNP: rs397514395
Type: Deletion
Location: chr3:15644789 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 291: 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.Ser291Asn Pathogenic/Likely pathogenic ★★ same residue
BTD c.250-15del Pathogenic/Likely pathogenic ★★ same condition
BTD p.Arg144fs Pathogenic/Likely pathogenic ★★ same condition
BTD p.Arg442fs Pathogenic/Likely pathogenic ★★ same condition
BTD p.Arg502fs Likely pathogenic ★★ same condition
BTD p.Cys15fs Pathogenic/Likely pathogenic ★★ same condition
BTD p.Gln116fs Pathogenic/Likely pathogenic ★★ same condition
BTD p.Gly14fs 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-ser291fs (accessed [today's date]).

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