Is EGR2 p.Ala309Pro (c.925G>C) pathogenic?

EGR2 p.Ala309Pro (c.925G>C) is classified Uncertain significance in EGR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: likely benign (0.2305); Very rare (popmax 0.000849%, nfe); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with EGR2 p.Ala309Pro (c.925G>C)?

EGR2 p.Ala309Pro (c.925G>C) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is EGR2 p.Ala309Pro (c.925G>C) in the general population?

EGR2 p.Ala309Pro (c.925G>C) is very rare (popmax 0.000849%, nfe) (gnomAD).

What do computational predictors say about EGR2 p.Ala309Pro (c.925G>C)?

AlphaMissense predicts likely benign (score 0.2305) — an in-silico prediction, not a clinical call.

EGR2 p.Ala309Pro

c.925G>C · rs2492296070 · VCV2916409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2305 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.2305	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.9, phastCons 0.69
Regional constraint	o/e 0.80	unconstrained · MANE · 728 bp · p 0.00043 · regional, not allelic
Overall
CADD	17.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000849% European (non-Finnish) · 10/1,178,196 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000687% 10/1,455,704 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.Ala309Pro
Coding: c.925G>C
MANE Select: NM_000399
dbSNP: rs2492296070
Type: single nucleotide variant
Location: chr10:62813713 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.02

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.Ala309Thr Uncertain significance ★ ⚠ same residue
EGR2 p.Ala309del Conflicting classifications of pathogenicity ★ same residue
EGR2 p.Ala309dup Conflicting classifications of pathogenicity ★ same residue
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

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-ala309pro (accessed [today's date]).

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