Is BTBD9 p.Val500Ile (c.1498G>A) pathogenic?

BTBD9 p.Val500Ile (c.1498G>A) is classified Uncertain significance in BTBD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0583); Ultra-rare (popmax 0.0494%, nfe).

How common is BTBD9 p.Val500Ile (c.1498G>A) in the general population?

BTBD9 p.Val500Ile (c.1498G>A) is ultra-rare (popmax 0.0494%, nfe) (gnomAD).

What do computational predictors say about BTBD9 p.Val500Ile (c.1498G>A)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

BTBD9 p.Val500Ile

c.1498G>A · rs61757644 · VCV2510773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.29	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 1.4	GERP -0.65, phastCons 0.87
Regional constraint	o/e 0.78	unconstrained · MANE · 423 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	15.74	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 0.0494% European (non-Finnish) · 583/1,179,910 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0448%

Overall 0.0389% 628/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0494%	2,024
Finnishnot grpmax-eligible	0.0359%	2,784
Remaining individualsnot grpmax-eligible	0.0176%	5,682
African / African-American	0.008%	12,508
South Asian	0.00439%	22,765
Admixed American	0.00167%	60,018

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: BTBD9
Protein: p.Val500Ile
Coding: c.1498G>A
MANE Select: NM_001099272
dbSNP: rs61757644
Type: single nucleotide variant
Location: chr6:38256473 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71

Full BTBD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD9 p.Ala100Val Uncertain significance ★ ⚠ same type
BTBD9 p.Ala28Thr Uncertain significance ★ ⚠ same type
BTBD9 p.Ala476Thr Uncertain significance ★ ⚠ same type
BTBD9 p.Ala590Val Uncertain significance ★ ⚠ same type
BTBD9 p.Ala76Val Uncertain significance ★ ⚠ same type
BTBD9 p.Arg257Gly Uncertain significance ★ ⚠ same type
BTBD9 p.Arg319His Uncertain significance ★ ⚠ same type
BTBD9 p.Arg336Gly 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/btbd9-p-val500ile (accessed [today's date]).

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