# NM_004448.4(ERBB2):c.1064C>T (p.Ala355Val)

https://sugi.bio/variant/erbb2-p-ala355val

## Summary

**ERBB2 p.Ala355Val (c.1064C>T)** is classified **Uncertain significance** in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1678); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## 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.Ala355Val |
| Coding change (HGVS c.) | c.1064C>T |
| MANE Select transcript | [NM_004448](https://www.ncbi.nlm.nih.gov/nuccore/NM_004448) |
| Variant type | single nucleotide variant |
| Location | chr17:39712364-39712364 (GRCh38) |
| ClinVar | [VCV3611423](https://www.ncbi.nlm.nih.gov/clinvar/variation/3611423/) |

**All HGVS expressions:** `LRG_724:g.29225C>T`, `LRG_724t1:c.974C>T`, `LRG_724t2:c.1064C>T`, `LRG_724t3:c.974C>T`, `LRG_724t4:c.1019C>T`, `NC_000017.10:g.37868617C>T`, `NC_000017.11:g.39712364C>T`, `NG_007503.1:g.29225C>T`, `NM_001005862.3:c.974C>T`, `NM_001289936.2:c.1019C>T`, `NM_001289937.2:c.1064C>T`, `NM_001289938.2:c.974C>T`, `NM_001382782.1:c.974C>T`, `NM_001382783.1:c.974C>T`, `NM_001382784.1:c.1064C>T`, `NM_001382785.1:c.1064C>T`, `NM_001382786.1:c.1064C>T`, `NM_001382787.1:c.1139C>T`, `NM_001382788.1:c.1064C>T`, `NM_001382789.1:c.1064C>T`, `NM_001382790.1:c.1064C>T`, `NM_001382791.1:c.1055C>T`, `NM_001382792.1:c.1064C>T`, `NM_001382793.1:c.1064C>T`, `NM_001382794.1:c.1064C>T`, `NM_001382795.1:c.1064C>T`, `NM_001382796.1:c.1064C>T`, `NM_001382797.1:c.1064C>T`, `NM_001382798.1:c.1064C>T`, `NM_001382799.1:c.884C>T`, `NM_001382800.1:c.1064C>T`, `NM_001382801.1:c.1064C>T`, `NM_001382802.1:c.806C>T`, `NM_001382803.1:c.1064C>T`, `NM_001382804.1:c.236C>T`, `NM_001382805.1:c.1064C>T`, `NM_001382806.1:c.1064C>T`, `NM_004448.4:c.1064C>T`, `NR_110535.2:n.1302C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1678)
- REVEL 0.275 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.975 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.702, GERP 2.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.0**. 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 0.71** across the covering region of the MANE Select transcript (39,707,123–39,723,431), spanning 16,308 bp. Chi-square p 1.3e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.25**, donor loss **0.01**, acceptor gain **0.07**, donor gain **0.00**. Largest is acceptor loss, 42 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.07**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,864 in the highest group · 1/1,461,458 alleles overall — very rare (popmax 0.00223%, eas).

*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 **355** lies in a disulfide bond.

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. 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 2024-10-15.

**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 | 2024-10-15 |

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

## Similar variants {#similar}

Related ERBB2 variant pages (same residue, condition, or type): [ERBB2 p.Ala355=](/variant/erbb2-p-ala355), [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).

### 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 3611423). 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.*