# NM_004327.4(BCR):c.1239C>G (p.Ile413Met)

https://sugi.bio/variant/bcr-p-ile413met

## Summary

**BCR p.Ile413Met (c.1239C>G)** is classified **Likely benign** in BCR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: ambiguous (0.4311); Rare (popmax 0.165%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs56321828 · 2 submitters · AlphaMissense ambiguous · rare (popmax 0.165%, mid)

## For patients & families {#patients}

This is a change in the BCR gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [BCR](https://sugi.bio/atlas/gene/BCR/) |
| Protein change (HGVS p.) | p.Ile413Met |
| Coding change (HGVS c.) | c.1239C>G |
| MANE Select transcript | [NM_004327](https://www.ncbi.nlm.nih.gov/nuccore/NM_004327) |
| dbSNP | [rs56321828](https://www.ncbi.nlm.nih.gov/snp/rs56321828/) |
| Variant type | single nucleotide variant |
| Location | chr22:23182199-23182199 (GRCh38) |
| ClinVar | [VCV732727](https://www.ncbi.nlm.nih.gov/clinvar/variation/732727/) |

**All HGVS expressions:** `LRG_1112:g.6835C>G`, `LRG_1112t1:c.1239C>G`, `NC_000022.10:g.23524386C>G`, `NC_000022.11:g.23182199C>G`, `NG_009244.2:g.6835C>G`, `NM_004327.4:c.1239C>G`, `NM_021574.3:c.1239C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4311) — no call either way
- REVEL 0.216 (benign-leaning)
- SaProt LLR -6.584 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 0.541, GERP -3.83, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 22.2**. 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 1.27** across the covering region of the MANE Select transcript (23,180,961–23,253,817), spanning 72,856 bp. Chi-square p 1.1e-11. 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 (gnomAD v4.1): grpmax **0.165%** (mid) · FAF95 0.1% · FAF99 0.0982% · 10/6,046 in the highest group · 1,465/1,592,832 alleles overall — rare (popmax 0.165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.256% | 391 |
| Middle Eastern (grpmax) | 0.165% | 605 |
| European (non-Finnish) | 0.105% | 952 |
| Remaining individuals (not grpmax-eligible) | 0.0937% | 1,068 |
| Admixed American | 0.0219% | 4,563 |
| South Asian | 0.0122% | 8,205 |
| African / African-American | 0.00935% | 10,699 |

Finnish shows a higher raw frequency than the grpmax group. 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.

*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}

**BCR** population constraint: LOEUF 0.608, pLI 6.2898e-06, missense-Z -0.17793; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **413** lies in a UniProt-annotated variant site (in); the 'kinase' region.

AlphaFold model confidence (whole protein): pLDDT 65.61, 23% of residues very-high.

**5 experimental structure(s)** (PDB): [1K1F](https://www.rcsb.org/structure/1K1F), [2AIN](https://www.rcsb.org/structure/2AIN), [5N6R](https://www.rcsb.org/structure/5N6R), [5N7E](https://www.rcsb.org/structure/5N7E), [5OC7](https://www.rcsb.org/structure/5OC7).

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

*Describes the biological roles of BCR (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:** BCR's established molecular role includes guanyl-nucleotide exchange factor activity. p.Ile413Met falls in the kinase region. In Reactome, BCR is annotated in disease pathway(s) including **Signaling by FGFR1 in disease**, **Signaling by cytosolic FGFR1 fusion mutants**.

**Disease mechanism (Reactome):** BCR loss or alteration is curated in [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302), [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117).

### Pathways affected {#pathways}

BCR participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117) | curated |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, GTPase activator activity.

**Biological process:** small GTPase-mediated signal transduction, keratinocyte differentiation, regulation of Rho protein signal transduction, focal adhesion assembly, activation of GTPase activity.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related BCR variant pages (same residue, condition, or type): [BCR p.Ser356Arg](/variant/bcr-p-ser356arg), [BCR c.2116-6C>G](/variant/bcr-c-2116-minus-6c-g), [BCR c.2116-7C>A](/variant/bcr-c-2116-minus-7c-a), [BCR c.2526+7G>T](/variant/bcr-c-2526-plus-7g-t), [BCR c.3073-8T>C](/variant/bcr-c-3073-minus-8t-c), [BCR c.3183-4G>A](/variant/bcr-c-3183-minus-4g-a), [BCR p.Ala1257=](/variant/bcr-p-ala1257), [BCR p.Ala152Val](/variant/bcr-p-ala152val).

### 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 732727). 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.*