Is SKI p.Ala540= (c.1620G>A) pathogenic?

SKI p.Ala540= (c.1620G>A) is classified Likely benign in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-08). Ultra-rare (popmax 0.0167%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Ala540= (c.1620G>A) in the general population?

SKI p.Ala540= (c.1620G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

SKI p.Ala540=

Q: What condition is associated with SKI p.Ala540= (c.1620G>A)?

SKI p.Ala540= (c.1620G>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.1620G>A · rs529842293 · VCV415898

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

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 -9.2	GERP -3.8
Overall
CADD	4.435	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/6,004 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000501%

Overall 0.00102% 16/1,561,152 alleles · ultra-rare exomes 12/1,408,786 · genomes 4/152,366 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,004
African / African-American	0.00408%	24,497
Admixed American	0.00379%	26,359
Remaining individualsnot grpmax-eligible	0.00331%	30,253
East Asian	0.00241%	41,452
Finnishnot grpmax-eligible	0.0017%	58,760
South Asian	0.00118%	84,858
European (non-Finnish)	0.000433%	230,743

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.Ala540=
Coding: c.1620G>A
MANE Select: NM_003036
dbSNP: rs529842293
Type: single nucleotide variant
Location: chr1:2304438 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 540: 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.Ala540Val Conflicting classifications of pathogenicity ★ ⚠ 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
SKI p.Leu32Val 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-ala540 (accessed [today's date]).

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