Is SKI p.Ala482= (c.1446G>A) pathogenic?

SKI p.Ala482= (c.1446G>A) is classified Benign/Likely benign in SKI (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.01%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Ala482= (c.1446G>A) in the general population?

SKI p.Ala482= (c.1446G>A) is low-frequency (popmax 1.01%, nfe) (gnomAD).

SKI p.Ala482=

Q: What condition is associated with SKI p.Ala482= (c.1446G>A)?

SKI p.Ala482= (c.1446G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, Shprintzen-Goldberg syndrome (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.1446G>A · rs114345135 · VCV139115

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, nfe)

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 -20	GERP -3.8
Overall
CADD	1.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.01% European (non-Finnish) · 11,946/1,179,906 alleles

Filtering AF 0.997% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.991%

Overall 0.839% 13,526/1,612,576 alleles · low-frequency exomes 12,679/1,460,244 · genomes 847/152,332 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.01%	99
Finnishnot grpmax-eligible	0.973%	103
Remaining individualsnot grpmax-eligible	0.788%	127
Amishnot grpmax-eligible	0.439%	228
Admixed American	0.27%	370
South Asian	0.178%	562
African / African-American	0.163%	615
Middle Eastern	0.133%	752
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
East Asian	0.00223%	44,862

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: SKI
Protein: p.Ala482=
Coding: c.1446G>A
MANE Select: NM_003036
dbSNP: rs114345135
Type: single nucleotide variant
Location: chr1:2304074 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 482: the 'disordered' region

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Shprintzen-Goldberg syndrome

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SKI p.Ala482Val Conflicting classifications of pathogenicity ★ ⚠ same residue
SKI p.Ala482_Glu483del Uncertain significance ★★ same residue
SKI p.Gly116Glu Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Arg Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Ser Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly34Cys Pathogenic ★★ ⚠ same condition
SKI p.Gly34Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
SKI p.Gly34Val 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/ski-p-ala482 (accessed [today's date]).

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