# NM_000399.5(EGR2):c.1190C>A (p.Pro397His)

https://sugi.bio/variant/egr2-p-pro397his

## Summary

**EGR2 p.Pro397His (c.1190C>A)** is classified **Conflicting classifications of pathogenicity** in EGR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-30). AlphaMissense: likely pathogenic (0.9857); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1D.

**At a glance:** Conflicting classifications of pathogenicity · review: No assertion criteria · rsID rs2492293699 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EGR2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 1D.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | EGR2 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009189/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EGR2](https://sugi.bio/atlas/gene/EGR2/) |
| Protein change (HGVS p.) | p.Pro397His |
| Coding change (HGVS c.) | c.1190C>A |
| MANE Select transcript | [NM_000399](https://www.ncbi.nlm.nih.gov/nuccore/NM_000399) |
| dbSNP | [rs2492293699](https://www.ncbi.nlm.nih.gov/snp/rs2492293699/) |
| Variant type | single nucleotide variant |
| Location | chr10:62813448-62813448 (GRCh38) |
| ClinVar | [VCV2431049](https://www.ncbi.nlm.nih.gov/clinvar/variation/2431049/) |

**All HGVS expressions:** `LRG_239:g.111453C>A`, `LRG_239t1:c.1190C>A`, `NC_000010.10:g.64573208G>T`, `NC_000010.11:g.62813448G>T`, `NG_008936.2:g.111453C>A`, `NM_000399.5:c.1190C>A`, `NM_001136177.3:c.1190C>A`, `NM_001136178.2:c.1190C>A`, `NM_001136179.3:c.1040C>A`, `NM_001321037.2:c.1040C>A`, `NM_001410931.1:c.1229C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9857)
- REVEL 0.542 (indeterminate)
- SaProt LLR -15.416 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.889, GERP 2.89, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in EGR2 (of 2,795 modeled).
- CADD: **PHRED 33.0**. 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 0.34** across the covering region of the MANE Select transcript (62,813,369–62,813,604), spanning 235 bp — the region is depleted of missense variation. Chi-square p 2.4e-12. 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: **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}

**EGR2** population constraint: LOEUF 0.401, pLI 0.99692, missense-Z 2.7999; 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):

- **Charcot-Marie-Tooth disease** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 49.02, 3% of residues very-high.

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

*Describes the biological roles of EGR2 (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:** EGR2's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

EGR2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | electronic |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, ubiquitin protein ligase binding, sequence-specific DNA binding.

**Biological process:** positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-06-30.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2016–2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Inherited Neuropathy Consortium Ii, University Of Miami | Pathogenic | no assertion criteria provided | clinical testing | 2020-06-30 |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 1D](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-1d/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 1D, ERG2-related disorder, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 1D, HEREDITARY MOTOR AND SENSORY NEUROPATHY 1D, HMSN ID, Charcot-Marie-Tooth disease, demyelinating, type 1d, ERG2-related disorders.

## Similar variants {#similar}

Related EGR2 variant pages (same residue, condition, or type): [EGR2 p.Pro397=](/variant/egr2-p-pro397), [EGR2 p.Arg359Trp](/variant/egr2-p-arg359trp), [EGR2 p.Arg381Cys](/variant/egr2-p-arg381cys), [EGR2 p.Arg381His](/variant/egr2-p-arg381his), [EGR2 p.Arg409Trp](/variant/egr2-p-arg409trp), [EGR2 p.Glu412Gly](/variant/egr2-p-glu412gly), [EGR2 p.Arg257Gln](/variant/egr2-p-arg257gln), [EGR2 c.169+10G>T](/variant/egr2-c-169-plus-10g-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 2431049). 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.*