Is ACTN2 c.697+33G>A pathogenic?

ACTN2 c.697+33G>A is classified Benign in ACTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-07-14). Common (popmax 56.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with myopathy, congenital, with structured cores and z-line abnormalities.

What condition is associated with ACTN2 c.697+33G>A?

ACTN2 c.697+33G>A is associated with myopathy, congenital, with structured cores and z-line abnormalities (ClinVar).

ACTN2 c.697+33G>A

Q: How common is ACTN2 c.697+33G>A in the general population?

ACTN2 c.697+33G>A is common (popmax 56.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs819640 · VCV671060

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 56.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

myopathy, congenital, with structured cores and z-line abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +33	near-intronic (+33 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.083	GERP -3.9
Non-coding constraint	Z 2.19	1 kb window · o/e 0.73 · regional · uncalibrated
Overall
CADD	1.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.7% African / African-American · 41,963/73,948 alleles

Filtering AF 56.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.1%

Overall 34.5% 536,906/1,557,376 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	56.7%	2
East Asian	54.8%	2
South Asian	51.5%	2
Middle Eastern	48.2%	2
Amishnot grpmax-eligible	44.7%	2
Admixed American	38.2%	3
Ashkenazi Jewishnot grpmax-eligible	37.1%	3
Remaining individualsnot grpmax-eligible	36.4%	3
European (non-Finnish)	30.7%	3
Finnishnot grpmax-eligible	29.2%	3

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: ACTN2
Coding: c.697+33G>A
MANE Select: NM_001103
dbSNP: rs819640
Type: single nucleotide variant
Location: chr1:236731347 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy, congenital, with structured cores and z-line abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same condition
ACTN2 c.127-3C>A Uncertain significance ★★ same condition
ACTN2 c.536+6C>G Uncertain significance ★★ same condition
ACTN2 c.698-1179G>A Uncertain significance ★★ same condition
ACTN2 c.*1001T>A Uncertain significance ★★ same condition
ACTN2 c.*128G>A Uncertain significance ★★ same condition
ACTN2 c.*1645C>G Uncertain significance ★★ same condition
ACTN2 c.*286T>C 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/actn2-c-697-plus-33g-a (accessed [today's date]).

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