Is BTD p.Arg59His (c.176G>A) pathogenic?

BTD p.Arg59His (c.176G>A) is classified Pathogenic/Likely pathogenic in BTD (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.3029); Very rare (popmax 0.00439%, sas); Associated with biotinidase deficiency.

What condition is associated with BTD p.Arg59His (c.176G>A)?

BTD p.Arg59His (c.176G>A) is associated with biotinidase deficiency (ClinVar).

How common is BTD p.Arg59His (c.176G>A) in the general population?

BTD p.Arg59His (c.176G>A) is very rare (popmax 0.00439%, sas) (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.Arg59His (c.176G>A)?

AlphaMissense predicts likely benign (score 0.3029) — an in-silico prediction, not a clinical call.

BTD p.Arg59His

c.176G>A · rs397514343 · VCV38567

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3029 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotinidase deficiency

Computational evidence

Protein change
AlphaMissense	0.3029	likely benign ⚠ discordant with ClinVar
REVEL	0.704	pathogenic-leaning
SaProt	LLR -9.22	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 5.8	GERP -1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	25.3	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 R79H vs ClinVar R59H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,086 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00112% 18/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,772
African / African-American	0.00267%	37,468
European (non-Finnish)	0.00102%	98,337

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.Arg59His
Coding: c.176G>A
MANE Select: NM_001370658
dbSNP: rs397514343
Type: single nucleotide variant
Location: chr3:15635615 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 59: 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.Arg59Cys Pathogenic/Likely pathogenic ★★ same residue
BTD p.Arg59= 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

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-arg59his (accessed [today's date]).

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