Is BTD p.Val437Ala (c.1310T>C) pathogenic?

BTD p.Val437Ala (c.1310T>C) is classified Uncertain significance in BTD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-13). AlphaMissense: likely benign (0.1062); Ultra-rare (popmax 0.0413%, afr); Associated with Inborn genetic diseases.

What condition is associated with BTD p.Val437Ala (c.1310T>C)?

BTD p.Val437Ala (c.1310T>C) is associated with Inborn genetic diseases, biotinidase deficiency (ClinVar).

How common is BTD p.Val437Ala (c.1310T>C) in the general population?

BTD p.Val437Ala (c.1310T>C) is ultra-rare (popmax 0.0413%, afr) (gnomAD).

What do computational predictors say about BTD p.Val437Ala (c.1310T>C)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

BTD p.Val437Ala

c.1310T>C · rs149690919 · VCV92398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -9.19	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 0.76	GERP 1.2, phastCons 0.55
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	13.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V457A vs ClinVar V437A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0413% African / African-American · 31/75,032 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00211% 34/1,614,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0413%	2,420
East Asian	0.00668%	14,962

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.Val437Ala
Coding: c.1310T>C
MANE Select: NM_001370658
dbSNP: rs149690919
Type: single nucleotide variant
Location: chr3:15645226 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77

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.Val437= Likely benign ★★ same residue
BTD p.Val437Met Pathogenic ★ ⚠ same residue
BTD p.Val437Leu 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

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-val437ala (accessed [today's date]).

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