Is BTK p.Ala2= (c.6C>T) pathogenic?

BTK p.Ala2= (c.6C>T) is classified Likely benign in BTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). Very rare (popmax 0.00257%, nfe); Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Ala2= (c.6C>T)?

BTK p.Ala2= (c.6C>T) is associated with isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Ala2= (c.6C>T) in the general population?

BTK p.Ala2= (c.6C>T) is very rare (popmax 0.00257%, nfe) (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.Ala2=

c.6C>T · rs372818780 · VCV1150450

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00257%, nfe)

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 0.39	GERP -5.5, phastCons 0.001
Overall
CADD	2.577	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00257% European (non-Finnish) · 23/895,442 alleles

Filtering AF 0.00171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00198% 24/1,211,505 alleles · very rare exomes 24/1,098,103 · genomes 0/113,402 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00257%	38,932
Remaining individualsnot grpmax-eligible	0.0021%	47,649

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.Ala2=
Coding: c.6C>T
MANE Select: NM_000061
dbSNP: rs372818780
Type: single nucleotide variant
Location: chrX:101375279 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 2: a modified residue (n-acetylalanine)

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 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
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-ala2 (accessed [today's date]).

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