Is SKI p.Pro423= (c.1269G>A) pathogenic?

SKI p.Pro423= (c.1269G>A) is classified Likely benign in SKI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.032%, afr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro423= (c.1269G>A)?

SKI p.Pro423= (c.1269G>A) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Pro423= (c.1269G>A) in the general population?

SKI p.Pro423= (c.1269G>A) is ultra-rare (popmax 0.032%, afr) (gnomAD).

SKI p.Pro423=

c.1269G>A · rs375600617 · VCV387432

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.6	GERP -3.8
Overall
CADD	1.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% African / African-American · 24/75,006 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0044% 71/1,612,214 alleles · ultra-rare exomes 59/1,459,982 · genomes 12/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,125
Remaining individualsnot grpmax-eligible	0.00481%	20,800
European (non-Finnish)	0.00339%	29,494
South Asian	0.0033%	30,345
Finnishnot grpmax-eligible	0.0016%	62,640

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.Pro423=
Coding: c.1269G>A
MANE Select: NM_003036
dbSNP: rs375600617
Type: single nucleotide variant
Location: chr1:2303897 (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.Pro423Leu 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-pro423 (accessed [today's date]).

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