Is ENO3 p.Ala331= (c.993C>T) pathogenic?

ENO3 p.Ala331= (c.993C>T) is classified Benign/Likely benign in ENO3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 5.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with glycogen storage disease due to muscle beta-enolase deficiency.

What condition is associated with ENO3 p.Ala331= (c.993C>T)?

ENO3 p.Ala331= (c.993C>T) is associated with glycogen storage disease due to muscle beta-enolase deficiency (ClinVar).

ENO3 p.Ala331=

Q: How common is ENO3 p.Ala331= (c.993C>T) in the general population?

ENO3 p.Ala331= (c.993C>T) is common (popmax 5.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.993C>T · rs2230257 · VCV324148

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

glycogen storage disease due to muscle beta-enolase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.4	GERP -3.7
Overall
CADD	0.959	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.1% African / African-American · 3,821/74,934 alleles

Filtering AF 4.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.91%

Overall 0.293% 4,728/1,614,034 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.1%	20
Admixed American	0.5%	200
Middle Eastern	0.462%	216
Remaining individualsnot grpmax-eligible	0.406%	246
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0254%	3,933
South Asian	0.0165%	6,071
East Asian	0.00223%	44,872

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.Ala331=
Coding: c.993C>T
MANE Select: NM_053013
dbSNP: rs2230257
Type: single nucleotide variant
Location: chr17:4956069 (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 331: an α-helix

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 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
ENO3 p.Arg32Gln 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-ala331 (accessed [today's date]).

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