Is SKI p.Pro328Ala (c.982C>G) pathogenic?

SKI p.Pro328Ala (c.982C>G) is classified Uncertain significance in SKI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-30). AlphaMissense: likely benign (0.0604); Very rare (popmax 8.47e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Pro328Ala (c.982C>G)?

SKI p.Pro328Ala (c.982C>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Pro328Ala (c.982C>G) in the general population?

SKI p.Pro328Ala (c.982C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SKI p.Pro328Ala (c.982C>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

SKI p.Pro328Ala

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.982C>G · rs2100916031 · VCV1768336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.77, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.2e-05% 1/1,613,582 alleles · very rare exomes 1/1,461,234 · genomes 0/152,348 · 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.Pro328Ala
Coding: c.982C>G
MANE Select: NM_003036
dbSNP: rs2100916031
Type: single nucleotide variant
Location: chr1:2302990 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 328: the 'disordered' region

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.Pro328Leu Uncertain significance ★★ ⚠ same residue
SKI p.Pro328Arg Uncertain significance ★ ⚠ same residue
SKI p.Pro328Ser 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-pro328ala (accessed [today's date]).

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