Is BTN2A2 p.Arg445Trp (c.1333C>T) pathogenic?

BTN2A2 p.Arg445Trp (c.1333C>T) is classified Uncertain significance in BTN2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1559); Very rare (popmax 0.005%, amr).

How common is BTN2A2 p.Arg445Trp (c.1333C>T) in the general population?

BTN2A2 p.Arg445Trp (c.1333C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about BTN2A2 p.Arg445Trp (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

BTN2A2 p.Arg445Trp

c.1333C>T · VCV3993572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -10.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -2.8, phastCons 0.033
Regional constraint	o/e 0.94	unconstrained · MANE · 9,142 bp · p 0.12 · regional, not allelic
Overall
CADD	22.1	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 0.005% Admixed American · 3/60,012 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00235% 38/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,004
European (non-Finnish)	0.00263%	38,066
East Asian	0.00223%	44,888
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00156%	64,042

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: BTN2A2
Protein: p.Arg445Trp
Coding: c.1333C>T
MANE Select: NM_006995
Type: single nucleotide variant
Location: chr6:26392728 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.50 · 1 PDB
Residue 445: a β-strand; the b30.2/spry domain

Full BTN2A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTN2A2 p.Arg445Pro Uncertain significance ★ ⚠ same residue
BTN2A2 p.Ala147Gly Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala199Thr Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala201Pro Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala210Ser Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala248Glu Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala248Pro Uncertain significance ★ ⚠ same type
BTN2A2 p.Ala254Thr 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/btn2a2-p-arg445trp (accessed [today's date]).

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