Is BTBD2 p.Val451Ile (c.1351G>A) pathogenic?

BTBD2 p.Val451Ile (c.1351G>A) is classified Uncertain significance in BTBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-24). AlphaMissense: ambiguous (0.4991); Very rare (popmax 0.00446%, eas).

How common is BTBD2 p.Val451Ile (c.1351G>A) in the general population?

BTBD2 p.Val451Ile (c.1351G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BTBD2 p.Val451Ile (c.1351G>A)?

AlphaMissense predicts ambiguous (score 0.4991) — an in-silico prediction, not a clinical call.

BTBD2 p.Val451Ile

c.1351G>A · rs149233510 · VCV3135416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.4991	ambiguous
REVEL	0.5	indeterminate
SaProt	LLR -8.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0062 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00198% 32/1,613,172 alleles · very rare exomes 32/1,460,846 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,433
European (non-Finnish)	0.00229%	43,697
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,054

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: BTBD2
Protein: p.Val451Ile
Coding: c.1351G>A
MANE Select: NM_017797
dbSNP: rs149233510
Type: single nucleotide variant
Location: chr19:1986895 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 1 PDB
Residue 451: a β-strand

Full BTBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD2 p.Ala201Ser Uncertain significance ★ ⚠ same type
BTBD2 p.Ala201Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala33Gly Uncertain significance ★ ⚠ same type
BTBD2 p.Ala37Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala3Thr Uncertain significance ★ ⚠ same type
BTBD2 p.Ala41Glu Uncertain significance ★ ⚠ same type
BTBD2 p.Ala42Ser Uncertain significance ★ ⚠ same type
BTBD2 p.Ala446Val Uncertain significance ★ ⚠ same type

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/btbd2-p-val451ile (accessed [today's date]).

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