Is ACTL9 p.Val380Leu (c.1138G>T) pathogenic?

ACTL9 p.Val380Leu (c.1138G>T) is classified Pathogenic in ACTL9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-01). Absent from gnomAD v4.1; Associated with spermatogenic failure 53.

What condition is associated with ACTL9 p.Val380Leu (c.1138G>T)?

ACTL9 p.Val380Leu (c.1138G>T) is associated with spermatogenic failure 53 (ClinVar).

How common is ACTL9 p.Val380Leu (c.1138G>T) in the general population?

ACTL9 p.Val380Leu (c.1138G>T) is absent from gnomAD v4.1 (gnomAD).

ACTL9 p.Val380Leu

c.1138G>T · rs532021673 · VCV1048626

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

spermatogenic failure 53

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.809	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,247 bp · p 0.2 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTL9
Protein: p.Val380Leu
Coding: c.1138G>T
MANE Select: NM_178525
dbSNP: rs532021673
Type: single nucleotide variant
Location: chr19:8697564 (GRCh38)
Gene constraint: LOEUF 1.575 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 87.56
Residue 380: a UniProt-annotated variant site (in spgf53; uncertain significance; reduces interaction with actl7a)

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

Disease context

spermatogenic failure 53 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTL9 p.Ser345Leu Pathogenic same condition
ACTL9 p.Tyr403Ter Pathogenic same condition
ACTL9 p.Glu401fs Uncertain significance ★ same condition
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

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-val380leu (accessed [today's date]).

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