Is BTK p.Phe583Ser (c.1748T>C) pathogenic?

BTK p.Phe583Ser (c.1748T>C) is classified Likely pathogenic in BTK (ClinVar, Single submitter, 2 submitters; last evaluated 2026-04-22). AlphaMissense: likely pathogenic (0.9959); Absent from gnomAD v4.1; Associated with Agammaglobulinaemia with absent BTK expression.

How common is BTK p.Phe583Ser (c.1748T>C) in the general population?

BTK p.Phe583Ser (c.1748T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BTK p.Phe583Ser (c.1748T>C)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

BTK p.Phe583Ser

Q: What condition is associated with BTK p.Phe583Ser (c.1748T>C)?

BTK p.Phe583Ser (c.1748T>C) is associated with Agammaglobulinaemia with absent BTK expression, Bruton-type agammaglobulinemia (ClinVar).

c.1748T>C · VCV4279077

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Agammaglobulinaemia with absent BTK expression

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic ✓ concordant with ClinVar
REVEL	0.953	strongly pathogenic-leaning
SaProt	LLR -15.40	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 11	GERP 3.4, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 7,667 bp · p 5.5e-21 · regional, not allelic
Overall
CADD	31.0	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.Phe583Ser
Coding: c.1748T>C
MANE Select: NM_000061
Type: single nucleotide variant
Location: chrX:101353872 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 583: a UniProt-annotated variant site (in xla); an α-helix; the protein kinase domain

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

Disease context

Agammaglobulinaemia with absent BTK expression

Also linked: Bruton-type agammaglobulinemia

Similar variants

BTK p.Phe583Val Likely pathogenic ★ same residue
BTK c.1103-2A>G Pathogenic/Likely pathogenic ★★ same condition
BTK c.1349+1G>A Pathogenic ★★ same condition
BTK c.588+1G>T Pathogenic ★★ same condition
BTK c.777-1G>A Pathogenic/Likely pathogenic ★★ same condition
BTK c.777-2A>G Pathogenic/Likely pathogenic ★★ same condition
BTK c.839+1G>C Likely pathogenic ★★ same condition
BTK c.840-1G>A 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-phe583ser (accessed [today's date]).

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