Is ACTN1 p.Asp562Glu (c.1686C>G) pathogenic?

ACTN1 p.Asp562Glu (c.1686C>G) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: ambiguous (0.4237); Very rare (popmax 0.00133%, afr).

How common is ACTN1 p.Asp562Glu (c.1686C>G) in the general population?

ACTN1 p.Asp562Glu (c.1686C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTN1 p.Asp562Glu (c.1686C>G)?

AlphaMissense predicts ambiguous (score 0.4237) — an in-silico prediction, not a clinical call.

ACTN1 p.Asp562Glu

c.1686C>G · VCV4694917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4237	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -4.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 32 kb · p 3.7e-34 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,926 alleles

Overall 0.000657% 1/152,222 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: ACTN1
Protein: p.Asp562Glu
Coding: c.1686C>G
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68883005 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 562: the 'interaction with ddn' region

Full ACTN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTN1 p.Asp562Asn Uncertain significance ★★ ⚠ same residue
ACTN1 p.Arg450Cys Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Glu225Lys Pathogenic ★★ same type
ACTN1 p.Leu547Pro Likely pathogenic ★★ ⚠ same type
ACTN1 p.Val105Ile Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Ala255Val Uncertain significance ★★ ⚠ same type

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/actn1-p-asp562glu (accessed [today's date]).

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