Is SKI p.Ala242= (c.726C>T) pathogenic?

SKI p.Ala242= (c.726C>T) is classified Likely benign in SKI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-16). Ultra-rare (popmax 0.0102%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ala242= (c.726C>T)?

SKI p.Ala242= (c.726C>T) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ala242= (c.726C>T) in the general population?

SKI p.Ala242= (c.726C>T) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

SKI p.Ala242=

c.726C>T · rs139227600 · VCV381375

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Conditions

Shprintzen-Goldberg syndrome

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 -3.9, phastCons 1
Overall
CADD	13.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0102% European (non-Finnish) · 120/1,179,864 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00794% 128/1,611,656 alleles · ultra-rare exomes 123/1,459,432 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,832
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0032%	31,207
East Asian	0.00223%	44,878

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.Ala242=
Coding: c.726C>T
MANE Select: NM_003036
dbSNP: rs139227600
Type: single nucleotide variant
Location: chr1:2229492 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB

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

Disease context

Shprintzen-Goldberg syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

SKI p.Ala242Thr 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
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-ala242 (accessed [today's date]).

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