Is SKI p.Pro35= (c.105G>A) pathogenic?

SKI p.Pro35= (c.105G>A) is classified Likely benign in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0237%, afr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro35= (c.105G>A)?

SKI p.Pro35= (c.105G>A) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Pro35= (c.105G>A) in the general population?

SKI p.Pro35= (c.105G>A) is ultra-rare (popmax 0.0237%, afr) (gnomAD).

SKI p.Pro35=

c.105G>A · rs778180778 · VCV386838

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, afr)

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 2.4	GERP -2.2, phastCons 1
Overall
CADD	12.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0237% African / African-American · 16/67,418 alleles

Filtering AF 0.0148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00196% 28/1,429,122 alleles · ultra-rare exomes 13/1,279,332 · genomes 15/149,790 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0237%	4,214
East Asian	0.0222%	4,495
Remaining individualsnot grpmax-eligible	0.00753%	13,287
European (non-Finnish)	9.19e-05%	1,087,600

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.Pro35=
Coding: c.105G>A
MANE Select: NM_003036
dbSNP: rs778180778
Type: single nucleotide variant
Location: chr1:2228871 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 35: a UniProt-annotated variant site (in sgs); an α-helix

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.Pro35Ser Pathogenic ★★ ⚠ same residue
SKI p.Pro35Ala Likely pathogenic ★ ⚠ same residue
SKI p.Pro35Gln Pathogenic ★ ⚠ same residue
SKI p.Pro35Leu Likely pathogenic ★ ⚠ same residue
SKI p.Pro35Arg 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

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-pro35 (accessed [today's date]).

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