Is ACTL9 p.Leu228Val (c.682C>G) pathogenic?

ACTL9 p.Leu228Val (c.682C>G) is classified Uncertain significance in ACTL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). Very rare (popmax 0.00754%, nfe).

How common is ACTL9 p.Leu228Val (c.682C>G) in the general population?

ACTL9 p.Leu228Val (c.682C>G) is very rare (popmax 0.00754%, nfe) (gnomAD).

ACTL9 p.Leu228Val

c.682C>G · rs987371604 · VCV2461581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.717	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.84, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,247 bp · p 0.2 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00754% European (non-Finnish) · 89/1,179,798 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00555% 89/1,603,154 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: ACTL9
Protein: p.Leu228Val
Coding: c.682C>G
MANE Select: NM_178525
dbSNP: rs987371604
Type: single nucleotide variant
Location: chr19:8698020 (GRCh38)
Gene constraint: LOEUF 1.575 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 87.56

Full ACTL9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL9 p.Ala174Asp Uncertain significance ★ same type
ACTL9 p.Ala174Thr Uncertain significance ★ same type
ACTL9 p.Ala187Ser Uncertain significance ★ same type
ACTL9 p.Ala319Ser Uncertain significance ★ same type
ACTL9 p.Ala361Thr Uncertain significance ★ same type
ACTL9 p.Ala388Asp Uncertain significance ★ same type
ACTL9 p.Ala392Gly Uncertain significance ★ same type
ACTL9 p.Arg130Leu 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/actl9-p-leu228val (accessed [today's date]).

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