Is BTK p.Ala622Pro (c.1864G>C) pathogenic?

BTK p.Ala622Pro (c.1864G>C) is classified Uncertain significance in BTK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-05). AlphaMissense: likely pathogenic (0.992); Absent from gnomAD v4.1; Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Ala622Pro (c.1864G>C)?

BTK p.Ala622Pro (c.1864G>C) is associated with isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Ala622Pro (c.1864G>C) in the general population?

BTK p.Ala622Pro (c.1864G>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.Ala622Pro (c.1864G>C)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

BTK p.Ala622Pro

c.1864G>C · rs2147424035 · VCV1059586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.992 · 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	0.992	likely pathogenic
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -14.35	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 7.6	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	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ala622Pro
Coding: c.1864G>C
MANE Select: NM_000061
dbSNP: rs2147424035
Type: single nucleotide variant
Location: chrX:101353238 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 622: a UniProt-annotated variant site (in xla); 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.Ala622fs 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
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-ala622pro (accessed [today's date]).

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