Is BTK p.Pro177= (c.531T>C) pathogenic?

BTK p.Pro177= (c.531T>C) is classified Benign/Likely benign in BTK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Low-frequency (popmax 2.27%, afr); Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Pro177= (c.531T>C)?

BTK p.Pro177= (c.531T>C) is associated with isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Pro177= (c.531T>C) in the general population?

BTK p.Pro177= (c.531T>C) is low-frequency (popmax 2.27%, 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.Pro177=

c.531T>C · rs148358153 · VCV530949

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.27%, 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 0.52	GERP 2.8, phastCons 0.85
Overall
CADD	10.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.27% African / African-American · 1,301/57,318 alleles

Filtering AF 2.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.13%

Overall 0.124% 1,498/1,210,264 alleles · low-frequency exomes 733/1,097,994 · genomes 765/112,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.27%	44
Admixed American	0.225%	445
Remaining individualsnot grpmax-eligible	0.158%	635
South Asian	0.00528%	18,949
European (non-Finnish)	0.00179%	55,947

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.Pro177=
Coding: c.531T>C
MANE Select: NM_000061
dbSNP: rs148358153
Type: single nucleotide variant
Location: chrX:101362230 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 177: the 'disordered' region

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-pro177 (accessed [today's date]).

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