# NM_001729.4(BTC):c.406A>G (p.Ile136Val)

https://sugi.bio/variant/btc-p-ile136val

## Summary

**BTC p.Ile136Val (c.406A>G)** is classified **Likely benign** in BTC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0613); Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BTC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BTC](https://sugi.bio/atlas/gene/BTC/) |
| Protein change (HGVS p.) | p.Ile136Val |
| Coding change (HGVS c.) | c.406A>G |
| MANE Select transcript | [NM_001729](https://www.ncbi.nlm.nih.gov/nuccore/NM_001729) |
| Variant type | single nucleotide variant |
| Location | chr4:74750595-74750595 (GRCh38) |
| ClinVar | [VCV3825966](https://www.ncbi.nlm.nih.gov/clinvar/variation/3825966/) |

**All HGVS expressions:** `NC_000004.11:g.75675805T>C`, `NC_000004.12:g.74750595T>C`, `NM_001316963.2:c.282-2446A>G`, `NM_001729.4:c.406A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0613)
- REVEL 0.007 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.834 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.508, GERP -4.6 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.049**. 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.*
- Regional missense constraint: **o/e 1.10** across the covering region of the MANE Select transcript (74,748,044–74,794,325), spanning 46,281 bp. Chi-square p 0.13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**BTC** population constraint: LOEUF 1.209, pLI 0.0093095, missense-Z -0.2717. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.51, 11% of residues very-high.

**4 experimental structure(s)** (PDB): [1IOX](https://www.rcsb.org/structure/1IOX), [1IP0](https://www.rcsb.org/structure/1IP0), [8U4J](https://www.rcsb.org/structure/8U4J), [8U4K](https://www.rcsb.org/structure/8U4K).

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

*Describes the biological roles of BTC (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:** BTC's established molecular role includes transmembrane receptor protein tyrosine kinase activator activity. In Reactome, BTC is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Inhibition of Signaling by Overexpressed EGFR**.

**Disease mechanism (Reactome):** BTC loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Inhibition of Signaling by Overexpressed EGFR](https://reactome.org/content/detail/R-HSA-5638303), [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565).

### Pathways affected {#pathways}

BTC participates in **28 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Inhibition of Signaling by Overexpressed EGFR](https://reactome.org/content/detail/R-HSA-5638303) | curated |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | curated |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | curated |
| [EGFR downregulation](https://reactome.org/content/detail/R-HSA-182971) | curated |
| [EGFR interacts with phospholipase C-gamma](https://reactome.org/content/detail/R-HSA-212718) | curated |
| [ERBB2 Activates PTK6 Signaling](https://reactome.org/content/detail/R-HSA-8847993) | curated |
| [ERBB2 Regulates Cell Motility](https://reactome.org/content/detail/R-HSA-6785631) | curated |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | curated |
| [GRB2 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-179812) | curated |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | curated |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | curated |
| [PI3K events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250342) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [SHC1 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-180336) | curated |
| [SHC1 events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250347) | curated |
| [Signaling by EGFR](https://reactome.org/content/detail/R-HSA-177929) | curated |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [Signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1236394) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | electronic |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | electronic |

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

**Molecular function:** transmembrane receptor protein tyrosine kinase activator activity, receptor ligand activity.

**Biological process:** epidermal growth factor receptor signaling pathway, ERBB4-ERBB4 signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-29 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BTC variant pages (same residue, condition, or type): [BTC p.Leu44Phe](/variant/btc-p-leu44phe), [BTC p.Ala5Val](/variant/btc-p-ala5val), [BTC p.Arg106Lys](/variant/btc-p-arg106lys), [BTC p.Arg146Trp](/variant/btc-p-arg146trp), [BTC p.Arg148Cys](/variant/btc-p-arg148cys), [BTC p.Arg37Ile](/variant/btc-p-arg37ile), [BTC p.Arg6Gly](/variant/btc-p-arg6gly), [BTC p.Arg6Trp](/variant/btc-p-arg6trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3825966). 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.*