Is BTBD2 p.Arg9Cys (c.25C>T) pathogenic?

BTBD2 p.Arg9Cys (c.25C>T) is classified Likely benign in BTBD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-30). AlphaMissense: ambiguous (0.5277); Rare (popmax 0.269%, nfe); Associated with BTBD2-related disorder.

What condition is associated with BTBD2 p.Arg9Cys (c.25C>T)?

BTBD2 p.Arg9Cys (c.25C>T) is associated with BTBD2-related disorder (ClinVar).

How common is BTBD2 p.Arg9Cys (c.25C>T) in the general population?

BTBD2 p.Arg9Cys (c.25C>T) is rare (popmax 0.269%, nfe) (gnomAD).

What do computational predictors say about BTBD2 p.Arg9Cys (c.25C>T)?

AlphaMissense predicts ambiguous (score 0.5277) — an in-silico prediction, not a clinical call.

BTBD2 p.Arg9Cys

c.25C>T · rs992604117 · VCV3032698

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5277 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.269%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

BTBD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.5277	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP -1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.86 · regional, not allelic
Overall
CADD	21.2	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 0.269% European (non-Finnish) · 2,243/835,190 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.256%

Overall 0.241% 2,372/985,998 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	7.1%	14
European (non-Finnish)grpmax	0.269%	372
Remaining individualsnot grpmax-eligible	0.156%	643
Ashkenazi Jewishnot grpmax-eligible	0.105%	953
Middle Eastern	0.0959%	1,043
African / African-American	0.0423%	2,367
Finnishnot grpmax-eligible	0.03%	3,330
Admixed American	0.0138%	7,265

Amish 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: BTBD2
Protein: p.Arg9Cys
Coding: c.25C>T
MANE Select: NM_017797
dbSNP: rs992604117
Type: single nucleotide variant
Location: chr19:2015679 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 1 PDB
Residue 9: the 'disordered' region

Full BTBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BTBD2-related disorder

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-arg9cys (accessed [today's date]).

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