Is BTBD16 p.Arg446Cys (c.1336C>T) pathogenic?

BTBD16 p.Arg446Cys (c.1336C>T) is classified Uncertain significance in BTBD16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.3358); Very rare (popmax 0.00502%, amr).

How common is BTBD16 p.Arg446Cys (c.1336C>T) in the general population?

BTBD16 p.Arg446Cys (c.1336C>T) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about BTBD16 p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.3358) — an in-silico prediction, not a clinical call.

BTBD16 p.Arg446Cys

c.1336C>T · VCV3261985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3358	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -12.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 63 kb · p 0.47 · regional, not allelic
Overall
CADD	24.1	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 0.00502% Admixed American · 3/59,732 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.00136% 22/1,613,010 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00502%	19,911
South Asian	0.0033%	30,287
Remaining individualsnot grpmax-eligible	0.0032%	31,236
African / African-American	0.00267%	37,427
East Asian	0.00223%	44,806
European (non-Finnish)	0.000932%	107,244

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: BTBD16
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_144587
Type: single nucleotide variant
Location: chr10:122336566 (GRCh38)
Gene constraint: LOEUF 1.246 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.92

Full BTBD16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD16 p.Ala113Val Uncertain significance ★ ⚠ same type
BTBD16 p.Ala161Thr Uncertain significance ★ ⚠ same type
BTBD16 p.Ala204Asp Uncertain significance ★ ⚠ same type
BTBD16 p.Ala362Thr Uncertain significance ★ ⚠ same type
BTBD16 p.Ala505Val Uncertain significance ★ ⚠ same type
BTBD16 p.Arg13Cys Uncertain significance ★ ⚠ same type
BTBD16 p.Arg197Ser Uncertain significance ★ ⚠ same type
BTBD16 p.Arg21Trp 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/btbd16-p-arg446cys (accessed [today's date]).

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