Is SKI p.Arg595= (c.1785C>G) pathogenic?

SKI p.Arg595= (c.1785C>G) is classified Likely benign in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-11). Ultra-rare (popmax 0.0254%, amr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Arg595= (c.1785C>G)?

SKI p.Arg595= (c.1785C>G) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Arg595= (c.1785C>G) in the general population?

SKI p.Arg595= (c.1785C>G) is ultra-rare (popmax 0.0254%, amr) (gnomAD).

SKI p.Arg595=

c.1785C>G · rs199727876 · VCV1780075

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, amr)

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 -13	GERP -3.5
Overall
CADD	0.061	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% Admixed American · 14/55,158 alleles

Filtering AF 0.0153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.00151% 24/1,588,448 alleles · ultra-rare exomes 8/1,436,122 · genomes 16/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0254%	3,940
African / African-American	0.00936%	10,687
Remaining individualsnot grpmax-eligible	0.00324%	30,830
European (non-Finnish)	8.55e-05%	1,169,314

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.Arg595=
Coding: c.1785C>G
MANE Select: NM_003036
dbSNP: rs199727876
Type: single nucleotide variant
Location: chr1:2306037 (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.Arg595Cys Uncertain significance ★ ⚠ same residue
SKI p.Arg595Leu Uncertain significance ★ ⚠ same residue
SKI p.Arg595His 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-arg595 (accessed [today's date]).

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