# NM_004448.4(ERBB2):c.3711C>A (p.Phe1237Leu)

https://sugi.bio/variant/erbb2-p-phe1237leu

## Summary

**ERBB2 p.Phe1237Leu (c.3711C>A)** is classified **Uncertain significance** in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.4335); Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ERBB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [ERBB2](https://sugi.bio/atlas/gene/ERBB2/) |
| Protein change (HGVS p.) | p.Phe1237Leu |
| Coding change (HGVS c.) | c.3711C>A |
| MANE Select transcript | [NM_004448](https://www.ncbi.nlm.nih.gov/nuccore/NM_004448) |
| Variant type | single nucleotide variant |
| Location | chr17:39727987-39727987 (GRCh38) |
| ClinVar | [VCV4762453](https://www.ncbi.nlm.nih.gov/clinvar/variation/4762453/) |

**All HGVS expressions:** `LRG_724:g.44848C>A`, `LRG_724t1:c.3621C>A`, `LRG_724t2:c.3711C>A`, `LRG_724t4:c.3666C>A`, `NC_000017.10:g.37884240C>A`, `NC_000017.11:g.39727987C>A`, `NG_007503.1:g.44848C>A`, `NM_001005862.3:c.3621C>A`, `NM_001289936.2:c.3666C>A`, `NM_001289937.2:c.*290C>A`, `NM_001382782.1:c.3621C>A`, `NM_001382783.1:c.3621C>A`, `NM_001382784.1:c.3828C>A`, `NM_001382785.1:c.3813C>A`, `NM_001382786.1:c.3792C>A`, `NM_001382787.1:c.3786C>A`, `NM_001382788.1:c.3741C>A`, `NM_001382789.1:c.3732C>A`, `NM_001382790.1:c.3708C>A`, `NM_001382791.1:c.3702C>A`, `NM_001382792.1:c.3675C>A`, `NM_001382793.1:c.3669C>A`, `NM_001382794.1:c.3669C>A`, `NM_001382795.1:c.3663C>A`, `NM_001382796.1:c.3624C>A`, `NM_001382797.1:c.3612C>A`, `NM_001382798.1:c.3555C>A`, `NM_001382799.1:c.3531C>A`, `NM_001382800.1:c.3525C>A`, `NM_001382801.1:c.3507C>A`, `NM_001382802.1:c.3453C>A`, `NM_001382803.1:c.*290C>A`, `NM_001382804.1:c.2883C>A`, `NM_001382805.1:c.2760C>A`, `NM_001382806.1:c.2673C>A`, `NM_004448.4:c.3711C>A`, `NR_110535.2:n.3949C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4335) — no call either way
- REVEL 0.19 (benign-leaning)
- SaProt LLR -3.876 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 0.506, GERP -0.871, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 8.733**. 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 0.91** across the covering region of the MANE Select transcript (39,726,826–39,728,041), spanning 1,215 bp. Chi-square p 0.086. 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 **0.00167%** (amr) · 1/59,994 in the highest group · 1/1,460,498 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**ERBB2** population constraint: LOEUF 0.518, pLI 0.063119, missense-Z 4.2475. *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 **1237** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 74.65, 43% of residues very-high.

**63 experimental structure(s)** (PDB): [1MFG](https://www.rcsb.org/structure/1MFG), [1MFL](https://www.rcsb.org/structure/1MFL), [1MW4](https://www.rcsb.org/structure/1MW4), [1N8Z](https://www.rcsb.org/structure/1N8Z), [1QR1](https://www.rcsb.org/structure/1QR1), [1S78](https://www.rcsb.org/structure/1S78) — incl. mutant structure 6BGT.

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

*Describes the biological roles of ERBB2 (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:** ERBB2's established molecular role includes RNA polymerase I core binding. p.Phe1237Leu falls in the disordered region. In Reactome, ERBB2 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Constitutive Signaling by Overexpressed ERBB2**.

**Disease mechanism (Reactome):** ERBB2 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285), [Drug resistance in ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665737).

### Pathways affected {#pathways}

ERBB2 participates in **33 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285) | curated |
| ⚕ [Drug resistance in ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665737) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to AEE788](https://reactome.org/content/detail/R-HSA-9665250) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to afatinib](https://reactome.org/content/detail/R-HSA-9665249) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to lapatinib](https://reactome.org/content/detail/R-HSA-9665251) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to neratinib](https://reactome.org/content/detail/R-HSA-9665246) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to osimertinib](https://reactome.org/content/detail/R-HSA-9665247) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to sapitinib](https://reactome.org/content/detail/R-HSA-9665244) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to tesevatinib](https://reactome.org/content/detail/R-HSA-9665245) | curated |
| ⚕ [Resistance of ERBB2 KD mutants to trastuzumab](https://reactome.org/content/detail/R-HSA-9665233) | curated |
| ⚕ [Signaling by ERBB2 ECD mutants](https://reactome.org/content/detail/R-HSA-9665348) | 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 |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | curated |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | curated |
| [Downregulation of ERBB2:ERBB3 signaling](https://reactome.org/content/detail/R-HSA-1358803) | curated |
| [Drug-mediated inhibition of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-9652282) | 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 |
| [GRB7 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1306955) | curated |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | 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 |
| [Sema4D induced cell migration and growth-cone collapse](https://reactome.org/content/detail/R-HSA-416572) | curated |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [TFAP2 (AP-2) family regulates transcription of growth factors and their receptors](https://reactome.org/content/detail/R-HSA-8866910) | curated |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | electronic |
| [PLCG1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1251932) | electronic |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | electronic |

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

**Molecular function:** RNA polymerase I core binding, protein tyrosine kinase activity, transmembrane receptor protein tyrosine kinase activity, transmembrane signaling receptor activity, signaling receptor binding, receptor tyrosine kinase binding.

**Biological process:** signal transduction, cell surface receptor signaling pathway, cell surface receptor protein tyrosine kinase signaling pathway, cell population proliferation, peptidyl-tyrosine phosphorylation, positive regulation of cell growth.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-22 |

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

## Similar variants {#similar}

Related ERBB2 variant pages (same residue, condition, or type): [ERBB2 p.Ala598Asp](/variant/erbb2-p-ala598asp), [ERBB2 p.Ala644Thr](/variant/erbb2-p-ala644thr), [ERBB2 p.Arg1048Cys](/variant/erbb2-p-arg1048cys), [ERBB2 p.Arg188Cys](/variant/erbb2-p-arg188cys), [ERBB2 p.Arg188His](/variant/erbb2-p-arg188his), [ERBB2 p.Arg190Gln](/variant/erbb2-p-arg190gln), [ERBB2 p.Arg203His](/variant/erbb2-p-arg203his), [ERBB2 p.Arg217Cys](/variant/erbb2-p-arg217cys).

### 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 4762453). 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.*