# NM_000061.3(BTK):c.1197A>G (p.Pro399=)

https://sugi.bio/variant/btk-p-pro399

## Summary

**BTK p.Pro399= (c.1197A>G)** is classified **Likely benign** in BTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-29). Very rare (popmax 0.000335%, nfe); Associated with isolated growth hormone deficiency type III.

**At a glance:** Likely benign · review: Single submitter · rsID rs1377590088 · 1 submitter · 1 linked condition · very rare (popmax 0.000335%, nfe)

## For patients & families {#patients}

This is a change in the BTK gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to isolated growth hormone deficiency type III.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | BTK is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Non-acquired isolated growth hormone deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Anterior hypopituitarism — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Delayed skeletal maturation — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Doll-like facies — Frequent (79-30%)
- Delayed puberty — Frequent (79-30%)
- Decreased response to growth hormone stimulation test — Frequent (79-30%)
- Abnormally high-pitched voice — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BTK](https://sugi.bio/atlas/gene/BTK/) |
| Protein change (HGVS p.) | p.Pro399= |
| Coding change (HGVS c.) | c.1197A>G |
| MANE Select transcript | [NM_000061](https://www.ncbi.nlm.nih.gov/nuccore/NM_000061) |
| dbSNP | [rs1377590088](https://www.ncbi.nlm.nih.gov/snp/rs1377590088/) |
| Variant type | single nucleotide variant |
| Location | chrX:101356936-101356936 (GRCh38) |
| ClinVar | [VCV2874148](https://www.ncbi.nlm.nih.gov/clinvar/variation/2874148/) |

**All HGVS expressions:** `LRG_128:g.34289A>G`, `LRG_128t1:c.1197A>G`, `NC_000023.10:g.100611924T>C`, `NC_000023.11:g.101356936T>C`, `NG_009616.1:g.34289A>G`, `NM_000061.3:c.1197A>G`, `NM_001287344.2:c.1299A>G`, `NM_001287345.2:c.1038+1438A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.547, GERP -3.53, phastCons 1 — weakly conserved position
- CADD: **PHRED 11.31**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.33 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000335%** (nfe) · FAF95 8.9e-05% · FAF99 2.5e-05% · 3/895,325 in the highest group · 3/1,210,516 alleles overall — very rare (popmax 0.000335%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BTK** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **isolated growth hormone deficiency type III** — Disputed (XL)
- **Bruton-type agammaglobulinemia** — Definitive (XL)

## Protein context {#protein}

Residue **399** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.95, 52% of residues very-high.

**170 experimental structure(s)** (PDB): [1AWW](https://www.rcsb.org/structure/1AWW), [1AWX](https://www.rcsb.org/structure/1AWX), [1B55](https://www.rcsb.org/structure/1B55), [1BTK](https://www.rcsb.org/structure/1BTK), [1BWN](https://www.rcsb.org/structure/1BWN), [1K2P](https://www.rcsb.org/structure/1K2P) — incl. mutant structure 1BTK.

## What this gene does {#gene-function}

*Describes the biological roles of BTK (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BTK's established molecular role includes protein tyrosine kinase activity. In Reactome, BTK is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**, **IRAK4 deficiency (TLR2/4)**.

**Disease mechanism (Reactome):** BTK loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422), [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041), [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498).

### Pathways affected {#pathways}

BTK participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| ⚕ [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041) | curated |
| ⚕ [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [G beta:gamma signalling through BTK](https://reactome.org/content/detail/R-HSA-8964315) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, phosphatidylinositol-3,4,5-trisphosphate binding, phospholipase activator activity, identical protein binding, phospholipase binding.

**Biological process:** peptidyl-tyrosine phosphorylation, intracellular signal transduction, B cell receptor signaling pathway, positive regulation of cGAS/STING signaling pathway, positive regulation of NLRP3 inflammasome complex assembly.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-29 |

## Associated conditions {#conditions}

[isolated growth hormone deficiency type III](https://sugi.bio/atlas/disease/isolated-growth-hormone-deficiency-type-iii/).

**Reported phenotype names (ClinVar):** X-linked agammaglobulinemia with growth hormone deficiency, AGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED, Isolated growth hormone deficiency type 3, Growth hormone deficiency with hypogammaglobulinemia, FLEISHER SYNDROME, HYPOGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED, IGHD III, ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA.

## Similar variants {#similar}

Related BTK variant pages (same residue, condition, or type): [BTK c.1103-2A>G](/variant/btk-c-1103-minus-2a-g), [BTK c.1349+1G>A](/variant/btk-c-1349-plus-1g-a), [BTK c.1632-2A>G](/variant/btk-c-1632-minus-2a-g), [BTK c.588+1G>T](/variant/btk-c-588-plus-1g-t), [BTK c.777-1G>A](/variant/btk-c-777-minus-1g-a), [BTK c.777-2A>G](/variant/btk-c-777-minus-2a-g), [BTK c.839+1G>C](/variant/btk-c-839-plus-1g-c), [BTK c.840-1G>A](/variant/btk-c-840-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2874148). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*