Is BTBD7 p.Arg289Gln (c.866G>A) pathogenic?

BTBD7 p.Arg289Gln (c.866G>A) is classified Uncertain significance in BTBD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.5202); Very rare (popmax 0.00339%, nfe).

How common is BTBD7 p.Arg289Gln (c.866G>A) in the general population?

BTBD7 p.Arg289Gln (c.866G>A) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about BTBD7 p.Arg289Gln (c.866G>A)?

AlphaMissense predicts ambiguous (score 0.5202) — an in-silico prediction, not a clinical call.

BTBD7 p.Arg289Gln

c.866G>A · VCV3993488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5202	ambiguous
REVEL	0.555	indeterminate
SaProt	LLR -7.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 32 kb · p 4.8e-10 · regional, not allelic
Overall
CADD	26.7	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 0.00339% European (non-Finnish) · 40/1,179,884 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00297% 48/1,613,474 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,613
European (non-Finnish)grpmax	0.00339%	29,497
African / African-American	0.00267%	37,413
East Asian	0.00223%	44,894
Finnishnot grpmax-eligible	0.00156%	63,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BTBD7
Protein: p.Arg289Gln
Coding: c.866G>A
MANE Select: NM_001002860
Type: single nucleotide variant
Location: chr14:93294154 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 61.50
Residue 289: the btb 2 domain

Full BTBD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD7 p.Ala110Thr Uncertain significance ★ ⚠ same type
BTBD7 p.Ala158Thr Uncertain significance ★ ⚠ same type
BTBD7 p.Ala359Ser Uncertain significance ★ ⚠ same type
BTBD7 p.Ala3Val Uncertain significance ★ ⚠ same type
BTBD7 p.Ala491Asp Uncertain significance ★ ⚠ same type
BTBD7 p.Ala567Ser Uncertain significance ★ ⚠ same type
BTBD7 p.Ala567Val Uncertain significance ★ ⚠ same type
BTBD7 p.Ala675Ser 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/btbd7-p-arg289gln (accessed [today's date]).

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