# NM_005228.5(EGFR):c.408C>T (p.Pro136=)

https://sugi.bio/variant/egfr-p-pro136

## Summary

**EGFR p.Pro136= (c.408C>T)** is classified **Likely benign** in EGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). Absent from gnomAD v4.1; Associated with EGFR-related lung cancer.

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

## For patients & families {#patients}

This is a change in the EGFR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Pro136= |
| Coding change (HGVS c.) | c.408C>T |
| MANE Select transcript | [NM_005228](https://www.ncbi.nlm.nih.gov/nuccore/NM_005228) |
| Variant type | single nucleotide variant |
| Location | chr7:55143472-55143472 (GRCh38) |
| ClinVar | [VCV4733416](https://www.ncbi.nlm.nih.gov/clinvar/variation/4733416/) |

**All HGVS expressions:** `LRG_304:g.129441C>T`, `LRG_304t1:c.408C>T`, `NC_000007.13:g.55211165C>T`, `NC_000007.14:g.55143472C>T`, `NG_007726.3:g.129441C>T`, `NM_001346897.2:c.408C>T`, `NM_001346898.2:c.408C>T`, `NM_001346899.2:c.408C>T`, `NM_001346900.2:c.249C>T`, `NM_001346941.2:c.89-12358C>T`, `NM_005228.5:c.408C>T`, `NM_201282.2:c.408C>T`, `NM_201283.2:c.408C>T`, `NM_201284.2:c.408C>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 -1.216, GERP -0.146 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.59**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for EGFR (1,537 scored positions, the nearest 7 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**EGFR** population constraint: LOEUF 0.475, pLI 0.98251, missense-Z 3.0635; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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 **136** lies in a UniProt-annotated variant site (variant egfr viii; found in a lung cancer sample; somatic mutation; induces lung cancer when exogenously expressed).

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 Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** EGFR-related lung cancer.

## Similar variants {#similar}

Related EGFR variant pages (same residue, condition, or type): [EGFR c.1499-3C>T](/variant/egfr-c-1499-minus-3c-t), [EGFR c.2061+5G>A](/variant/egfr-c-2061-plus-5g-a), [EGFR c.2061+5G>T](/variant/egfr-c-2061-plus-5g-t), [EGFR c.2062-3C>G](/variant/egfr-c-2062-minus-3c-g), [EGFR c.3114+4T>G](/variant/egfr-c-3114-plus-4t-g), [EGFR c.3271+3G>A](/variant/egfr-c-3271-plus-3g-a), [EGFR c.629-3C>T](/variant/egfr-c-629-minus-3c-t), [EGFR c.748-3T>C](/variant/egfr-c-748-minus-3t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4733416). 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.*