Is BTBD2 p.Arg281Trp (c.841C>T) pathogenic?

BTBD2 p.Arg281Trp (c.841C>T) is classified Uncertain significance in BTBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-12). AlphaMissense: ambiguous (0.438); Ultra-rare (popmax 0.012%, afr).

How common is BTBD2 p.Arg281Trp (c.841C>T) in the general population?

BTBD2 p.Arg281Trp (c.841C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about BTBD2 p.Arg281Trp (c.841C>T)?

AlphaMissense predicts ambiguous (score 0.438) — an in-silico prediction, not a clinical call.

BTBD2 p.Arg281Trp

c.841C>T · rs766935152 · VCV2407672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Computational evidence

Protein change
AlphaMissense	0.438	ambiguous
REVEL	0.477	indeterminate
SaProt	LLR -10.02	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.57, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0062 · regional, not allelic
Overall
CADD	27.5	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 0.012% African / African-American · 9/74,886 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00124% 20/1,610,648 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,321
East Asian	0.00447%	22,385
Remaining individualsnot grpmax-eligible	0.00321%	31,187
European (non-Finnish)	0.000594%	168,444

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.Arg281Trp
Coding: c.841C>T
MANE Select: NM_017797
dbSNP: rs766935152
Type: single nucleotide variant
Location: chr19:1990151 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 1 PDB

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-arg281trp (accessed [today's date]).

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