Is BTK p.Arg562Pro (c.1685G>C) pathogenic?

BTK p.Arg562Pro (c.1685G>C) is classified Pathogenic/Likely pathogenic in BTK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-22). AlphaMissense: likely pathogenic (0.9957); Absent from gnomAD v4.1; Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Arg562Pro (c.1685G>C)?

BTK p.Arg562Pro (c.1685G>C) is associated with isolated growth hormone deficiency type III, Bruton-type agammaglobulinemia (ClinVar).

How common is BTK p.Arg562Pro (c.1685G>C) in the general population?

BTK p.Arg562Pro (c.1685G>C) is absent from gnomAD v4.1 (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.

What do computational predictors say about BTK p.Arg562Pro (c.1685G>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

BTK p.Arg562Pro

c.1685G>C · rs104894770 · VCV11394

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated growth hormone deficiency type III

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic ✓ concordant with ClinVar
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -13.49	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 4.9	GERP 0.44, 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.Arg562Pro
Coding: c.1685G>C
MANE Select: NM_000061
dbSNP: rs104894770
Type: single nucleotide variant
Location: chrX:101353935 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 562: 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

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

Also linked: Bruton-type agammaglobulinemia

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.Arg562Trp Pathogenic ★★ same residue
BTK p.Arg562Gln Likely 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
BTK c.777-1G>A Pathogenic/Likely pathogenic ★★ same condition
BTK c.777-2A>G 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-arg562pro (accessed [today's date]).

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