# NM_005228.5(EGFR):c.1452C>T (p.Ser484=)

https://sugi.bio/variant/egfr-p-ser484

## Summary

**EGFR p.Ser484= (c.1452C>T)** is classified **Likely benign** in EGFR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0312%, eas); Associated with EGFR-related lung cancer.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs568681121 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0312%, eas)

## For patients & families {#patients}

This is a change in the EGFR gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to EGFR-related lung cancer.

*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 | [EGFR](https://sugi.bio/atlas/gene/EGFR/) |
| Protein change (HGVS p.) | p.Ser484= |
| Coding change (HGVS c.) | c.1452C>T |
| MANE Select transcript | [NM_005228](https://www.ncbi.nlm.nih.gov/nuccore/NM_005228) |
| dbSNP | [rs568681121](https://www.ncbi.nlm.nih.gov/snp/rs568681121/) |
| Variant type | single nucleotide variant |
| Location | chr7:55160292-55160292 (GRCh38) |
| ClinVar | [VCV1125008](https://www.ncbi.nlm.nih.gov/clinvar/variation/1125008/) |

**All HGVS expressions:** `LRG_304:g.146261C>T`, `LRG_304t1:c.1452C>T`, `NC_000007.13:g.55227985C>T`, `NC_000007.14:g.55160292C>T`, `NG_007726.3:g.146261C>T`, `NM_001346897.2:c.1317C>T`, `NM_001346898.2:c.1452C>T`, `NM_001346899.2:c.1317C>T`, `NM_001346900.2:c.1293C>T`, `NM_001346941.2:c.651C>T`, `NM_005228.3:c.1452C>T`, `NM_005228.5:c.1452C>T`, `NM_201282.2:c.1452C>T`, `NM_201284.2:c.1452C>T`

## 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 -1.001, GERP -3.8 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.81**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.41 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0312%** (eas) · FAF95 0.0188% · FAF99 0.0151% · 14/44,892 in the highest group · 36/1,613,786 alleles overall — ultra-rare (popmax 0.0312%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0312% | 3,207 |
| Middle Eastern | 0.0164% | 6,084 |
| African / African-American | 0.00267% | 37,464 |
| European (non-Finnish) | 0.00153% | 65,555 |
| South Asian | 0.0011% | 91,072 |

*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}

**EGFR** population constraint: LOEUF 0.475, pLI 0.98251, missense-Z 3.0635; 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.*

Curated gene–disease validity (ClinGen):

- **non-small cell lung carcinoma** — Definitive (AD)

## Protein context {#protein}

Residue **484** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 76.29, 48% of residues very-high.

**393 experimental structure(s)** (PDB): [1IVO](https://www.rcsb.org/structure/1IVO), [1M14](https://www.rcsb.org/structure/1M14), [1M17](https://www.rcsb.org/structure/1M17), [1MOX](https://www.rcsb.org/structure/1MOX), [1NQL](https://www.rcsb.org/structure/1NQL), [1XKK](https://www.rcsb.org/structure/1XKK) — incl. mutant structure 3IKA.

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

*Describes the biological roles of EGFR (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:** EGFR's established molecular role includes chromatin binding. In Reactome, EGFR is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Constitutive Signaling by EGFRvIII**.

**Disease mechanism (Reactome):** EGFR loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810), [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382).

### Pathways affected {#pathways}

EGFR participates in **37 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 EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | curated |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| ⚕ [Inhibition of Signaling by Overexpressed EGFR](https://reactome.org/content/detail/R-HSA-5638303) | curated |
| ⚕ [Respiratory syncytial virus (RSV) attachment and entry](https://reactome.org/content/detail/R-HSA-9820960) | 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 |
| [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 |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | curated |
| [EGFR Transactivation by Gastrin](https://reactome.org/content/detail/R-HSA-2179392) | 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 |
| [NOTCH3 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013507) | 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 |
| [PTK6 promotes HIF1A stabilization](https://reactome.org/content/detail/R-HSA-8857538) | 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 |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | 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 |
| [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:** chromatin binding, protein tyrosine kinase activity, transmembrane signaling receptor activity, epidermal growth factor receptor activity, enzyme binding, kinase binding.

**Biological process:** positive regulation of protein phosphorylation, signal transduction, cell surface receptor signaling pathway, epidermal growth factor receptor signaling pathway, positive regulation of cell population proliferation, positive regulation of cell growth.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-08 |

## Associated conditions {#conditions}

[EGFR-related lung cancer](https://sugi.bio/atlas/disease/egfr-related-lung-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** EGFR-related lung cancer, Hereditary cancer-predisposing syndrome, not specified, AllHighlyPenetrant, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related EGFR variant pages (same residue, condition, or type): [EGFR p.Ser484Ala](/variant/egfr-p-ser484ala), [EGFR p.Ser484Phe](/variant/egfr-p-ser484phe), [EGFR c.1207+5G>A](/variant/egfr-c-1207-plus-5g-a), [EGFR c.1298+3A>G](/variant/egfr-c-1298-plus-3a-g), [EGFR c.1298+4A>G](/variant/egfr-c-1298-plus-4a-g), [EGFR c.1298+6T>C](/variant/egfr-c-1298-plus-6t-c), [EGFR c.1499-3C>T](/variant/egfr-c-1499-minus-3c-t), [EGFR c.1499-4G>T](/variant/egfr-c-1499-minus-4g-t).

### 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 1125008). 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.*