Is BTBD3 p.Val433Ile (c.1297G>A) pathogenic?

BTBD3 p.Val433Ile (c.1297G>A) is classified Uncertain significance in BTBD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely benign (0.0599); Very rare (popmax 0.00534%, afr).

How common is BTBD3 p.Val433Ile (c.1297G>A) in the general population?

BTBD3 p.Val433Ile (c.1297G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about BTBD3 p.Val433Ile (c.1297G>A)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

BTBD3 p.Val433Ile

c.1297G>A · VCV3262013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -6.81	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 5,094 bp · p 2.4e-20 · regional, not allelic
Overall
CADD	23.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,936 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.0018% 29/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,734
Admixed American	0.00333%	30,005
South Asian	0.0022%	45,542
European (non-Finnish)	0.00178%	56,193

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: BTBD3
Protein: p.Val433Ile
Coding: c.1297G>A
MANE Select: NM_014962
Type: single nucleotide variant
Location: chr20:11923394 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 83.60

Full BTBD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD3 p.Val433Ala Uncertain significance ★ ⚠ same residue
BTBD3 p.Ala303= Benign ★★ same type
BTBD3 p.Ala176Thr Uncertain significance ★ ⚠ same type
BTBD3 p.Ala189Thr Uncertain significance ★ ⚠ same type
BTBD3 p.Ala200Ser Uncertain significance ★ same type
BTBD3 p.Ala303Val Uncertain significance ★ ⚠ same type
BTBD3 p.Ala73Asp Uncertain significance ★ ⚠ same type
BTBD3 p.Ala96Val 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/btbd3-p-val433ile (accessed [today's date]).

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