# NM_000061.3(BTK):c.1662A>C (p.Ser554=)

https://sugi.bio/variant/btk-p-ser554

## Summary

**BTK p.Ser554= (c.1662A>C)** is classified **Likely benign** in BTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). Very rare (popmax 0.000112%, nfe); Associated with isolated growth hormone deficiency type III.

**At a glance:** Likely benign · review: Single submitter · rsID rs2520534663 · 1 submitter · 1 linked condition · very rare (popmax 0.000112%, 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.Ser554= |
| Coding change (HGVS c.) | c.1662A>C |
| MANE Select transcript | [NM_000061](https://www.ncbi.nlm.nih.gov/nuccore/NM_000061) |
| dbSNP | [rs2520534663](https://www.ncbi.nlm.nih.gov/snp/rs2520534663/) |
| Variant type | single nucleotide variant |
| Location | chrX:101353958-101353958 (GRCh38) |
| ClinVar | [VCV2810047](https://www.ncbi.nlm.nih.gov/clinvar/variation/2810047/) |

**All HGVS expressions:** `LRG_128:g.37267A>C`, `LRG_128t1:c.1662A>C`, `NC_000023.10:g.100608946T>G`, `NC_000023.11:g.101353958T>G`, `NG_009616.1:g.37267A>C`, `NG_011734.1:g.12A>C`, `NM_000061.3:c.1662A>C`, `NM_001287344.2:c.1764A>C`, `NM_001287345.2:c.1134A>C`

## 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 -0.471, GERP -5.21, phastCons 0.131 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.922**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/892,917 in the highest group · 1/1,209,284 alleles overall — very rare (popmax 0.000112%, 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 **554** lies in the protein kinase domain.

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. p.Ser554= falls in the protein kinase domain. 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 2023-01-17.

**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 | 2023-01-17 |

## 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, FLEISHER SYNDROME, HYPOGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED, IGHD III, Isolated growth hormone deficiency type 3, Growth hormone deficiency with hypogammaglobulinemia, 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 2810047). 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.*