Is ACTN1 p.Ala698Val (c.2093C>T) pathogenic?

ACTN1 p.Ala698Val (c.2093C>T) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.5025); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACTN1 p.Ala698Val (c.2093C>T)?

ACTN1 p.Ala698Val (c.2093C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACTN1 p.Ala698Val (c.2093C>T) in the general population?

ACTN1 p.Ala698Val (c.2093C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTN1 p.Ala698Val (c.2093C>T)?

AlphaMissense predicts ambiguous (score 0.5025) — an in-silico prediction, not a clinical call.

ACTN1 p.Ala698Val

c.2093C>T · VCV4221721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5025 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5025	ambiguous
REVEL	0.317	indeterminate
SaProt	LLR -12.47	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 32 kb · p 3.7e-34 · regional, not allelic
Overall
CADD	34.0	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 · 1/74,912 alleles

Overall 0.000657% 1/152,118 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.Ala698Val
Coding: c.2093C>T
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68880850 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 698: the 'interaction with ddn' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN1 p.Ala698= Likely benign ★★ same residue
ACTN1 p.Ala48Val Uncertain significance ★★ ⚠ same condition
ACTN1 p.Arg475His Uncertain significance ★★ same condition
ACTN1 p.Asn824Ser Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp11Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Gly Uncertain significance ★★ ⚠ same condition
ACTN1 p.Glu273Lys 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/actn1-p-ala698val (accessed [today's date]).

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