Is ACTL9 p.Ser8Pro (c.22T>C) pathogenic?

ACTL9 p.Ser8Pro (c.22T>C) is classified Likely benign in ACTL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). Very rare (popmax 8.87e-05%, nfe).

How common is ACTL9 p.Ser8Pro (c.22T>C) in the general population?

ACTL9 p.Ser8Pro (c.22T>C) is very rare (popmax 8.87e-05%, nfe) (gnomAD).

ACTL9 p.Ser8Pro

c.22T>C · rs2512731821 · VCV2618609

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.87e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.227	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.51	GERP -2.3
Regional constraint	o/e 1.05	unconstrained · MANE · 1,247 bp · p 0.2 · regional, not allelic
Overall
CADD	0.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.87e-05% European (non-Finnish) · 1/1,127,936 alleles

Overall 6.58e-05% 1/1,520,892 alleles · very rare exomes 1/1,369,236 · genomes 0/151,656 · joint denominator

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.Ser8Pro
Coding: c.22T>C
MANE Select: NM_178525
dbSNP: rs2512731821
Type: single nucleotide variant
Location: chr19:8698680 (GRCh38)
Gene constraint: LOEUF 1.575 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 87.56
Residue 8: the 'disordered' region

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

Similar variants

ACTL9 p.Ser8Tyr Uncertain significance ★ same residue
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

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-ser8pro (accessed [today's date]).

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