Is EGR2 p.Pro339Ser (c.1015C>T) pathogenic?

EGR2 p.Pro339Ser (c.1015C>T) is classified Uncertain significance in EGR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.6828); Very rare (popmax 6.85e-05%); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with EGR2 p.Pro339Ser (c.1015C>T)?

EGR2 p.Pro339Ser (c.1015C>T) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is EGR2 p.Pro339Ser (c.1015C>T) in the general population?

EGR2 p.Pro339Ser (c.1015C>T) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about EGR2 p.Pro339Ser (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.6828) — an in-silico prediction, not a clinical call.

EGR2 p.Pro339Ser

c.1015C>T · VCV3710361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.6828	likely pathogenic
REVEL	0.422	indeterminate
SaProt	LLR -15.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 728 bp · p 0.00043 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.85e-05%

Overall 6.85e-05% 1/1,460,622 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EGR2
Protein: p.Pro339Ser
Coding: c.1015C>T
MANE Select: NM_000399
Type: single nucleotide variant
Location: chr10:62813623 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.02
Residue 339: the 'disordered' region

Full EGR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGR2 p.Arg359Trp Pathogenic ★★ same condition
EGR2 p.Arg381Cys Pathogenic ★★ same condition
EGR2 p.Arg381His Pathogenic ★★ same condition
EGR2 p.Arg381Leu Pathogenic ★★ same condition
EGR2 p.Arg409Gln Pathogenic/Likely pathogenic ★★ same condition
EGR2 p.Arg409Trp Pathogenic/Likely pathogenic ★★ same condition
EGR2 p.Glu356Gln Likely pathogenic ★★ ⚠ same condition
EGR2 p.Glu356Lys Pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/egr2-p-pro339ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown