# NM_001963.6(EGF):c.2904C>T (p.Ser968=)

https://sugi.bio/variant/egf-p-ser968

## Summary

**EGF p.Ser968= (c.2904C>T)** is classified **Likely benign** in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-07). Very rare (popmax 0.0022%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs771648861 · 1 submitter · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the EGF gene that is classified as likely benign — not considered disease-causing, 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 | [EGF](https://sugi.bio/atlas/gene/EGF/) |
| Protein change (HGVS p.) | p.Ser968= |
| Coding change (HGVS c.) | c.2904C>T |
| MANE Select transcript | [NM_001963](https://www.ncbi.nlm.nih.gov/nuccore/NM_001963) |
| dbSNP | [rs771648861](https://www.ncbi.nlm.nih.gov/snp/rs771648861/) |
| Variant type | single nucleotide variant |
| Location | chr4:109994779-109994779 (GRCh38) |
| ClinVar | [VCV1990403](https://www.ncbi.nlm.nih.gov/clinvar/variation/1990403/) |

**All HGVS expressions:** `NC_000004.11:g.110915935C>T`, `NC_000004.12:g.109994779C>T`, `NG_011441.2:g.86896C>T`, `NM_001178130.3:c.2781C>T`, `NM_001178131.3:c.2778C>T`, `NM_001357021.2:c.2535C>T`, `NM_001963.6:c.2904C>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 -1.716, GERP -4.05 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.184**. 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>G, Δ0.47 donor gain), 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 **0.0022%** (sas) · FAF95 0.000542% · FAF99 0.000428% · 2/91,084 in the highest group · 15/1,613,960 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,542 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |
| European (non-Finnish) | 0.00102% | 98,332 |

*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}

**EGF** population constraint: LOEUF 0.741, pLI 1.3128e-17, missense-Z 2.2238. *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):

- **renal hypomagnesemia 4** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.66, 21% of residues very-high.

**13 experimental structure(s)** (PDB): [1IVO](https://www.rcsb.org/structure/1IVO), [1JL9](https://www.rcsb.org/structure/1JL9), [1NQL](https://www.rcsb.org/structure/1NQL), [1P9J](https://www.rcsb.org/structure/1P9J), [2KV4](https://www.rcsb.org/structure/2KV4), [3NJP](https://www.rcsb.org/structure/3NJP).

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

*Describes the biological roles of EGF (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:** EGF's established molecular role includes guanyl-nucleotide exchange factor activity. In Reactome, EGF is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Constitutive Signaling by EGFRvIII**.

**Disease mechanism (Reactome):** EGF 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}

EGF 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 |
| ⚕ [Inhibition of Signaling by Overexpressed EGFR](https://reactome.org/content/detail/R-HSA-5638303) | 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 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 Multipotent Pancreatic Progenitor Cells](https://reactome.org/content/detail/R-HSA-9937080) | curated |
| [Developmental Lineage of Pancreatic Endocrine Mid Progenitor Cells](https://reactome.org/content/detail/R-HSA-9981148) | curated |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | 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 |
| [NFE2L2 regulating tumorigenic genes](https://reactome.org/content/detail/R-HSA-9818030) | 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 |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | 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 |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [Signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1236394) | 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 |
| [Signaling by EGFR](https://reactome.org/content/detail/R-HSA-177929) | electronic |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, growth factor activity, transmembrane receptor protein tyrosine kinase activator activity, receptor ligand activity.

**Biological process:** angiogenesis, positive regulation of endothelial cell proliferation, positive regulation of receptor internalization, epidermal growth factor receptor signaling pathway, positive regulation of cell population proliferation, positive regulation of endothelial cell migration.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-07.

**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 | 2025-07-07 |

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

## Similar variants {#similar}

Related EGF variant pages (same residue, condition, or type): [EGF c.2221+4C>T](/variant/egf-c-2221-plus-4c-t), [EGF c.2858-11G>T](/variant/egf-c-2858-minus-11g-t), [EGF c.-60C>T](/variant/egf-c-minus-60c-t), [EGF p.Ala1025Ser](/variant/egf-p-ala1025ser), [EGF p.Ala1037Val](/variant/egf-p-ala1037val), [EGF p.Ala45Val](/variant/egf-p-ala45val), [EGF p.Ala862Thr](/variant/egf-p-ala862thr), [EGF p.Arg213Gln](/variant/egf-p-arg213gln).

### 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 1990403). 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.*