Is SKI p.Ser480Trp (c.1439C>G) pathogenic?

SKI p.Ser480Trp (c.1439C>G) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: ambiguous (0.4415); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Ser480Trp (c.1439C>G)?

SKI p.Ser480Trp (c.1439C>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ser480Trp (c.1439C>G) in the general population?

SKI p.Ser480Trp (c.1439C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SKI p.Ser480Trp (c.1439C>G)?

AlphaMissense predicts ambiguous (score 0.4415) — an in-silico prediction, not a clinical call.

SKI p.Ser480Trp

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.1439C>G · rs367916348 · VCV3223057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4415 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4415	ambiguous
REVEL	0.562	indeterminate
SaProt	LLR -10.93	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	26.8	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.Ser480Trp
Coding: c.1439C>G
MANE Select: NM_003036
dbSNP: rs367916348
Type: single nucleotide variant
Location: chr1:2304067 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 480: the 'disordered' region; a modified residue (phosphoserine)

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.Ser480= Benign/Likely benign ★★ same residue
SKI p.Ser480Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SKI p.Ser480Pro Uncertain significance ★ ⚠ 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-ser480trp (accessed [today's date]).

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