Is SKI p.Asp669= (c.2007C>T) pathogenic?

SKI p.Asp669= (c.2007C>T) is classified Likely benign in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-27). Ultra-rare (popmax 0.0123%, eas); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Asp669= (c.2007C>T)?

SKI p.Asp669= (c.2007C>T) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Asp669= (c.2007C>T) in the general population?

SKI p.Asp669= (c.2007C>T) is ultra-rare (popmax 0.0123%, eas) (gnomAD).

SKI p.Asp669=

c.2007C>T · rs750838146 · VCV432935

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, eas)

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 2.1	GERP -0.4, phastCons 1
Overall
CADD	10.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% East Asian · 5/40,732 alleles

Filtering AF 0.00481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00123% 19/1,542,766 alleles · ultra-rare exomes 13/1,390,598 · genomes 6/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0123%	8,146
Admixed American	0.00786%	12,721
Remaining individualsnot grpmax-eligible	0.00669%	14,944
African / African-American	0.00275%	36,363
South Asian	0.00119%	83,830
European (non-Finnish)	0.000262%	381,827

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.Asp669=
Coding: c.2007C>T
MANE Select: NM_003036
dbSNP: rs750838146
Type: single nucleotide variant
Location: chr1:2306585 (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.Asp669Glu Benign/Likely benign ★★ same residue
SKI p.Asp669Gly Uncertain significance ★ same residue
SKI p.Asp669Asn 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

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-asp669 (accessed [today's date]).

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