Is ACTC1 p.His90= (c.270C>T) pathogenic?

ACTC1 p.His90= (c.270C>T) is classified Conflicting classifications of pathogenicity in ACTC1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with ACTC1 p.His90= (c.270C>T)?

ACTC1 p.His90= (c.270C>T) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is ACTC1 p.His90= (c.270C>T) in the general population?

ACTC1 p.His90= (c.270C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ACTC1 p.His90=

c.270C>T · rs138812333 · VCV136280

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -4.7
Overall
CADD	4.059	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00297% 48/1,614,190 alleles · ultra-rare exomes 42/1,461,892 · genomes 6/152,298 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00381%	26,223
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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: ACTC1
Protein: p.His90=
Coding: c.270C>T
MANE Select: NM_005159
dbSNP: rs138812333
Type: single nucleotide variant
Location: chr15:34793429 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 90: a UniProt-annotated variant site (in cmh11); an α-helix

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy hypertrophic cardiomyopathy hypertrophic cardiomyopathy 11 atrial septal defect 5 dilated cardiomyopathy 1R

Similar variants

ACTC1 p.His90Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Gly345Val Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Pro266Leu Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Ala297Ser Pathogenic ★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ same condition
ACTC1 p.Thr128Ile Likely 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/actc1-p-his90 (accessed [today's date]).

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