Is BTK p.Pro340Ser (c.1018C>T) pathogenic?

BTK p.Pro340Ser (c.1018C>T) is classified Uncertain significance in BTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-26). AlphaMissense: likely benign (0.1336); Very rare (popmax 0.00296%, eas); Associated with isolated growth hormone deficiency type III.

What condition is associated with BTK p.Pro340Ser (c.1018C>T)?

BTK p.Pro340Ser (c.1018C>T) is associated with isolated growth hormone deficiency type III (ClinVar).

How common is BTK p.Pro340Ser (c.1018C>T) in the general population?

BTK p.Pro340Ser (c.1018C>T) is very rare (popmax 0.00296%, eas) (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.Pro340Ser (c.1018C>T)?

AlphaMissense predicts likely benign (score 0.1336) — an in-silico prediction, not a clinical call.

BTK p.Pro340Ser

c.1018C>T · rs782303652 · VCV2124317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

isolated growth hormone deficiency type III

Computational evidence

Protein change
AlphaMissense	0.1336	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 3.4, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 17 kb · p 4.9e-19 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00296% East Asian · 1/33,839 alleles

Overall 0.000248% 3/1,211,902 alleles · very rare exomes 3/1,097,977 · genomes 0/113,925 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0042%	23,828
East Asiangrpmax	0.00296%	33,839

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro340Ser
Coding: c.1018C>T
MANE Select: NM_000061
dbSNP: rs782303652
Type: single nucleotide variant
Location: chrX:101358394 (GRCh38)
Structure: AlphaFold pLDDT 84.95 · 170 PDB
Residue 340: a turn; the sh2 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 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-pro340ser (accessed [today's date]).

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