Is BTK p.Pro566= (c.1698G>A) pathogenic?

BTK p.Pro566= (c.1698G>A) is classified Benign/Likely benign in BTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-02). Ultra-rare (popmax 0.0696%, afr); Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Pro566= (c.1698G>A)?

BTK p.Pro566= (c.1698G>A) is associated with isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Pro566= (c.1698G>A) in the general population?

BTK p.Pro566= (c.1698G>A) is ultra-rare (popmax 0.0696%, afr) (gnomAD).

How is Non-acquired isolated growth hormone deficiency inherited?

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

BTK p.Pro566=

c.1698G>A · rs3208812 · VCV1533713

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0696%, afr)

Conditions

isolated growth hormone deficiency type III

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 -0.017	GERP -0.13, phastCons 0.92
Overall
CADD	8.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0696% African / African-American · 40/57,433 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0466%

Overall 0.00777% 94/1,210,378 alleles · ultra-rare exomes 48/1,097,884 · genomes 46/112,494 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0696%	1,436
Admixed American	0.0654%	1,529
Remaining individualsnot grpmax-eligible	0.0357%	2,801
Middle Eastern	0.023%	4,351
South Asian	0.00703%	14,216
European (non-Finnish)	0.000223%	447,533

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.Pro566=
Coding: c.1698G>A
MANE Select: NM_000061
dbSNP: rs3208812
Type: single nucleotide variant
Location: chrX:101353922 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 566: an α-helix; the protein kinase domain

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

Disease context

isolated growth hormone deficiency type III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-acquired isolated growth hormone deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

BTK p.Pro566Arg Pathogenic ★ same residue
BTK p.Pro566Ser Likely pathogenic ★ same residue
BTK p.Pro566Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BTK p.Pro566fs Pathogenic ★ 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

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-pro566 (accessed [today's date]).

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