Is ACTA1 p.Arg41Ter (c.121C>T) pathogenic?

ACTA1 p.Arg41Ter (c.121C>T) is classified Pathogenic in ACTA1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-16). Very rare (popmax 0.00017%, nfe); Associated with congenital myopathy 2b, severe infantile, autosomal recessive.

What condition is associated with ACTA1 p.Arg41Ter (c.121C>T)?

ACTA1 p.Arg41Ter (c.121C>T) is associated with congenital myopathy 2b, severe infantile, autosomal recessive (ClinVar).

How common is ACTA1 p.Arg41Ter (c.121C>T) in the general population?

ACTA1 p.Arg41Ter (c.121C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Rigid spine syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ACTA1 p.Arg41Ter

c.121C>T · rs1429699993 · VCV2443895

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

congenital myopathy 2b, severe infantile, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.78, phastCons 1
Overall
CADD	45.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,742 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,240 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: ACTA1
Protein: p.Arg41Ter
Coding: c.121C>T
MANE Select: NM_001100
dbSNP: rs1429699993
Type: single nucleotide variant
Location: chr1:229432995 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB

Full ACTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myopathy 2b, severe infantile, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rigid spine syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACTA1 p.Arg41Leu Likely pathogenic ★ same residue
ACTA1 p.Arg41Gly Uncertain significance ★ ⚠ same residue
ACTA1 p.Glu261Val Pathogenic/Likely pathogenic ★★ same condition
ACTA1 p.Gly17Arg Pathogenic/Likely pathogenic ★★ same condition
ACTA1 p.Leu96Pro Pathogenic/Likely pathogenic ★★ same condition
ACTA1 p.Val154Leu Likely pathogenic ★ same condition
ACTA1 p.Tyr93His Uncertain significance ★ ⚠ same condition
ACTA1 c.809-1G>T Pathogenic 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/acta1-p-arg41ter (accessed [today's date]).

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