Is ACTL8 p.Val280Leu (c.838G>C) pathogenic?

ACTL8 p.Val280Leu (c.838G>C) is classified Uncertain significance in ACTL8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.2048); Very rare (popmax 0.0011%, sas).

How common is ACTL8 p.Val280Leu (c.838G>C) in the general population?

ACTL8 p.Val280Leu (c.838G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACTL8 p.Val280Leu (c.838G>C)?

AlphaMissense predicts likely benign (score 0.2048) — an in-silico prediction, not a clinical call.

ACTL8 p.Val280Leu

c.838G>C · VCV3483933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2048	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.6	GERP -3.6
Regional constraint	o/e 0.88	unconstrained · MANE · 609 bp · p 0.046 · regional, not allelic
Overall
CADD	0.016	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,026 alleles

Overall 0.000137% 2/1,460,376 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,026
European (non-Finnish)	8.48e-05%	1,179,248

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: ACTL8
Protein: p.Val280Leu
Coding: c.838G>C
MANE Select: NM_030812
Type: single nucleotide variant
Location: chr1:17826256 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 88.51

Full ACTL8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL8 p.Ala168Thr Uncertain significance ★ ⚠ same type
ACTL8 p.Ala182Val Uncertain significance ★ ⚠ same type
ACTL8 p.Ala205Thr Uncertain significance ★ ⚠ same type
ACTL8 p.Ala221Thr Uncertain significance ★ ⚠ same type
ACTL8 p.Ala221Val Uncertain significance ★ ⚠ same type
ACTL8 p.Arg111Gln Uncertain significance ★ ⚠ same type
ACTL8 p.Arg164Cys Uncertain significance ★ ⚠ same type
ACTL8 p.Arg164His 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/actl8-p-val280leu (accessed [today's date]).

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