Is ENO3 p.Val22= (c.66G>A) pathogenic?

ENO3 p.Val22= (c.66G>A) is classified Likely benign in ENO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-08). Very rare (popmax 0.00167%, amr); Associated with glycogen storage disease due to muscle beta-enolase deficiency.

What condition is associated with ENO3 p.Val22= (c.66G>A)?

ENO3 p.Val22= (c.66G>A) is associated with glycogen storage disease due to muscle beta-enolase deficiency (ClinVar).

How common is ENO3 p.Val22= (c.66G>A) in the general population?

ENO3 p.Val22= (c.66G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

ENO3 p.Val22=

Q: How is Glycogen storage disease due to muscle beta-enolase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.66G>A · rs373571348 · VCV1604065

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

glycogen storage disease due to muscle beta-enolase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.26	loss · gain 0.24 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 3.8	GERP -2.4, phastCons 1
Overall
CADD	18.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,614,054 alleles · very rare exomes 9/1,461,856 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	0.000847%	118,003

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: ENO3
Protein: p.Val22=
Coding: c.66G>A
MANE Select: NM_053013
dbSNP: rs373571348
Type: single nucleotide variant
Location: chr17:4951895 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.63 · 1 PDB
Residue 22: a β-strand

Full ENO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease due to muscle beta-enolase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle beta-enolase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

ENO3 p.Val22Met Uncertain significance ★★ ⚠ same residue
ENO3 c.1067+1G>A Uncertain significance ★★ same condition
ENO3 p.Ala159Pro Uncertain significance ★★ ⚠ same condition
ENO3 p.Ala39Thr Uncertain significance ★★ ⚠ same condition
ENO3 p.Arg183Cys Uncertain significance ★★ ⚠ same condition
ENO3 p.Arg253His Uncertain significance ★★ ⚠ same condition
ENO3 p.Arg269Gln Uncertain significance ★★ ⚠ same condition
ENO3 p.Arg30Ter Uncertain significance ★★ 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/eno3-p-val22 (accessed [today's date]).

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