Is SKI p.Ser366Arg (c.1096A>C) pathogenic?

SKI p.Ser366Arg (c.1096A>C) is classified Uncertain significance in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.5511); Very rare (popmax 0.00237%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ser366Arg (c.1096A>C)?

SKI p.Ser366Arg (c.1096A>C) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ser366Arg (c.1096A>C) in the general population?

SKI p.Ser366Arg (c.1096A>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about SKI p.Ser366Arg (c.1096A>C)?

AlphaMissense predicts ambiguous (score 0.5511) — an in-silico prediction, not a clinical call.

SKI p.Ser366Arg

c.1096A>C · rs1269741981 · VCV1330633

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.5511	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -3.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	16.64	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,179,960 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00174% 28/1,613,338 alleles · very rare exomes 28/1,461,174 · genomes 0/152,164 · joint denominator

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.Ser366Arg
Coding: c.1096A>C
MANE Select: NM_003036
dbSNP: rs1269741981
Type: single nucleotide variant
Location: chr1:2303285 (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.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
SKI p.Pro35Ser 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-ser366arg (accessed [today's date]).

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