Is BTBD9 p.Arg99Trp (c.295C>T) pathogenic?

BTBD9 p.Arg99Trp (c.295C>T) is classified Uncertain significance in BTBD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.5903); Rare (popmax 0.111%, eas).

How common is BTBD9 p.Arg99Trp (c.295C>T) in the general population?

BTBD9 p.Arg99Trp (c.295C>T) is rare (popmax 0.111%, eas) (gnomAD).

What do computational predictors say about BTBD9 p.Arg99Trp (c.295C>T)?

AlphaMissense predicts likely pathogenic (score 0.5903) — an in-silico prediction, not a clinical call.

BTBD9 p.Arg99Trp

c.295C>T · rs150015110 · VCV3135460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5903 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5903	likely pathogenic
REVEL	0.672	pathogenic-leaning
SaProt	LLR -12.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.77, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 423 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.111% East Asian · 50/44,880 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0781%

Overall 0.00421% 68/1,614,140 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.111%	898
South Asian	0.00878%	11,385
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.000593%	168,575

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.Arg99Trp
Coding: c.295C>T
MANE Select: NM_001099272
dbSNP: rs150015110
Type: single nucleotide variant
Location: chr6:38594218 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71
Residue 99: the btb domain

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

Similar variants

BTBD9 p.Arg99Gln Uncertain significance ★ ⚠ same residue
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

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-arg99trp (accessed [today's date]).

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