Is BTK p.Ser659= (c.1977C>T) pathogenic?

BTK p.Ser659= (c.1977C>T) is classified Conflicting classifications of pathogenicity in BTK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0355%, eas); Associated with Bruton-type agammaglobulinemia.

What condition is associated with BTK p.Ser659= (c.1977C>T)?

BTK p.Ser659= (c.1977C>T) is associated with Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Ser659= (c.1977C>T) in the general population?

BTK p.Ser659= (c.1977C>T) is ultra-rare (popmax 0.0355%, eas) (gnomAD).

How is Non-syndromic agammaglobulinemia inherited?

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

BTK p.Ser659=

c.1977C>T · rs782047787 · VCV913516

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0355%, eas)

Conditions

Bruton-type agammaglobulinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.47, phastCons 1
Overall
CADD	8.246	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0355% East Asian · 12/33,815 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00124% 15/1,206,445 alleles · ultra-rare exomes 15/1,093,517 · genomes 0/112,928 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0355%	2,818
Remaining individualsnot grpmax-eligible	0.00421%	23,729
European (non-Finnish)	0.000112%	891,226

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: BTK
Protein: p.Ser659=
Coding: c.1977C>T
MANE Select: NM_000061
dbSNP: rs782047787
Type: single nucleotide variant
Location: chrX:101349888 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 659: a modified residue (phosphoserine)

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

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.Ser659_Ter660delinsXaa 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
BTK c.777-2A>G Pathogenic/Likely pathogenic ★★ same condition
BTK c.839+1G>C 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-ser659 (accessed [today's date]).

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