Is BTD p.His303Arg (c.908A>G) pathogenic?

BTD p.His303Arg (c.908A>G) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-06-29). AlphaMissense: likely benign (0.276); Low-frequency (popmax 1.59%, sas); Associated with Fetal anomalies with a likely genetic cause.

What condition is associated with BTD p.His303Arg (c.908A>G)?

BTD p.His303Arg (c.908A>G) is associated with Fetal anomalies with a likely genetic cause, biotinidase deficiency (ClinVar).

How common is BTD p.His303Arg (c.908A>G) in the general population?

BTD p.His303Arg (c.908A>G) is low-frequency (popmax 1.59%, sas) (gnomAD).

What do computational predictors say about BTD p.His303Arg (c.908A>G)?

AlphaMissense predicts likely benign (score 0.276) — an in-silico prediction, not a clinical call.

BTD p.His303Arg

c.908A>G · rs397507176 · VCV38278

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.276 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.59%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fetal anomalies with a likely genetic cause

Computational evidence

Protein change
AlphaMissense	0.276	likely benign
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -5.91	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 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	24.7	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 H323R vs ClinVar H303R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.59% South Asian · 1,450/91,082 alleles

Filtering AF 1.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5%

Overall 0.0952% 1,537/1,614,216 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.59%	63
Remaining individualsnot grpmax-eligible	0.101%	992
Middle Eastern	0.066%	1,516
African / African-American	0.00266%	37,525
European (non-Finnish)	0.00153%	65,557

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.His303Arg
Coding: c.908A>G
MANE Select: NM_001370658
dbSNP: rs397507176
Type: single nucleotide variant
Location: chr3:15644824 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 303: a UniProt-annotated variant site (in btd deficiency; partial); the cn hydrolase domain

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

Disease context

Fetal anomalies with a likely genetic cause

Also linked: biotinidase deficiency

Similar variants

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
BTD p.Ala279Pro 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-his303arg (accessed [today's date]).

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