Is BTD p.Val276Ile (c.826G>A) pathogenic?

BTD p.Val276Ile (c.826G>A) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.0673); Ultra-rare (popmax 0.0666%, amr); Associated with Inborn genetic diseases.

What condition is associated with BTD p.Val276Ile (c.826G>A)?

BTD p.Val276Ile (c.826G>A) is associated with Inborn genetic diseases, biotinidase deficiency (ClinVar).

How common is BTD p.Val276Ile (c.826G>A) in the general population?

BTD p.Val276Ile (c.826G>A) is ultra-rare (popmax 0.0666%, amr) (gnomAD).

What do computational predictors say about BTD p.Val276Ile (c.826G>A)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

BTD p.Val276Ile

c.826G>A · rs185225945 · VCV2083175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -4.7
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	0.539	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 V296I vs ClinVar V276I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0666% Admixed American · 40/60,028 alleles

Filtering AF 0.0502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0031% 50/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0666%	1,501
South Asian	0.00329%	30,360
African / African-American	0.00267%	37,516
European (non-Finnish)	0.000424%	236,008

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.Val276Ile
Coding: c.826G>A
MANE Select: NM_001370658
dbSNP: rs185225945
Type: single nucleotide variant
Location: chr3:15644742 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 276: the cn hydrolase domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: biotinidase deficiency

Similar variants

BTD p.Val276Gly Conflicting classifications of pathogenicity ★ ⚠ 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
BTD p.Ala269Val 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-val276ile (accessed [today's date]).

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