Is BTD p.Arg128His (c.383G>A) pathogenic?

BTD p.Arg128His (c.383G>A) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1043); Ultra-rare (popmax 0.0103%, nfe); Associated with BTD-related disorder.

What condition is associated with BTD p.Arg128His (c.383G>A)?

BTD p.Arg128His (c.383G>A) is associated with BTD-related disorder, biotinidase deficiency (ClinVar).

How common is BTD p.Arg128His (c.383G>A) in the general population?

BTD p.Arg128His (c.383G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about BTD p.Arg128His (c.383G>A)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

BTD p.Arg128His

c.383G>A · rs367902696 · VCV25005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BTD-related disorder

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -8.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.24, phastCons 0.77
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	26.6	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 R148H vs ClinVar R128H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 121/1,180,014 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00855% 138/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,752
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00534%	18,734
Admixed American	0.005%	20,003
South Asian	0.00439%	22,765

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.Arg128His
Coding: c.383G>A
MANE Select: NM_001370658
dbSNP: rs367902696
Type: single nucleotide variant
Location: chr3:15642041 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 128: the cn hydrolase domain

Full BTD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BTD-related disorder

Also linked: biotinidase deficiency

Similar variants

BTD p.Arg128Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BTD p.Arg128Gly 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

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-arg128his (accessed [today's date]).

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