Is BTK p.Arg288Gln (c.863G>A) pathogenic?

BTK p.Arg288Gln (c.863G>A) is classified Pathogenic in BTK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-17). AlphaMissense: likely pathogenic (0.995); Absent from gnomAD v4.1; Associated with Bruton-type agammaglobulinemia.

What condition is associated with BTK p.Arg288Gln (c.863G>A)?

BTK p.Arg288Gln (c.863G>A) is associated with Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III, autosomal recessive agammaglobulinemia 1 (ClinVar).

How common is BTK p.Arg288Gln (c.863G>A) in the general population?

BTK p.Arg288Gln (c.863G>A) is absent from gnomAD v4.1 (gnomAD).

How is Non-syndromic agammaglobulinemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BTK p.Arg288Gln (c.863G>A)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

BTK p.Arg288Gln

c.863G>A · rs1555978277 · VCV492813

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bruton-type agammaglobulinemia

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic ✓ concordant with ClinVar
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -14.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.4, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 17 kb · p 4.9e-19 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BTK
Protein: p.Arg288Gln
Coding: c.863G>A
MANE Select: NM_000061
dbSNP: rs1555978277
Type: single nucleotide variant
Location: chrX:101359324 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 288: an α-helix; the sh2 domain; a UniProt-annotated variant site (in xla)

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

Disease context

Bruton-type agammaglobulinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated growth hormone deficiency type III autosomal recessive agammaglobulinemia 1

For Non-syndromic agammaglobulinemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

BTK p.Arg288Trp Pathogenic/Likely pathogenic ★★ same residue
BTK p.Arg288Gly Pathogenic ★ same residue
BTK p.Arg288Pro Uncertain significance ★ ⚠ same residue
BTK c.1103-2A>G Pathogenic/Likely pathogenic ★★ same condition
BTK c.1349+1G>A Pathogenic ★★ same condition
BTK c.1632-2A>G Pathogenic ★★ same condition
BTK c.588+1G>T Pathogenic ★★ same condition
BTK c.777-1G>A Pathogenic/Likely pathogenic ★★ same condition

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/btk-p-arg288gln (accessed [today's date]).

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