Is SKI p.Arg216Pro (c.647G>C) pathogenic?

SKI p.Arg216Pro (c.647G>C) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). AlphaMissense: ambiguous (0.3723); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Arg216Pro (c.647G>C)?

SKI p.Arg216Pro (c.647G>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Arg216Pro (c.647G>C) in the general population?

SKI p.Arg216Pro (c.647G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SKI p.Arg216Pro (c.647G>C)?

AlphaMissense predicts ambiguous (score 0.3723) — an in-silico prediction, not a clinical call.

SKI p.Arg216Pro

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.647G>C · rs1399726894 · VCV2566894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.3723	ambiguous
REVEL	0.608	indeterminate
SaProt	LLR -5.72	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.77, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 220 bp · p 6e-08 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SKI
Protein: p.Arg216Pro
Coding: c.647G>C
MANE Select: NM_003036
dbSNP: rs1399726894
Type: single nucleotide variant
Location: chr1:2229413 (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

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SKI p.Arg216His Uncertain significance ★★ ⚠ same residue
SKI p.Arg216Leu Uncertain significance ★ ⚠ same residue
SKI p.Arg216= Likely benign ★ same residue
SKI p.Pro35Ser Pathogenic ★★ ⚠ same condition
SKI p.Thr180Met Pathogenic/Likely pathogenic ★★ same condition
SKI c.1999-3C>T Uncertain significance ★★ same condition
SKI p.Ala208Pro Uncertain significance ★★ ⚠ same condition
SKI p.Ala208Val Uncertain significance ★★ ⚠ 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-arg216pro (accessed [today's date]).

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