Is SKI p.Ile110Val (c.328A>G) pathogenic?

SKI p.Ile110Val (c.328A>G) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely benign (0.258); Very rare (popmax 0.000254%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Ile110Val (c.328A>G)?

SKI p.Ile110Val (c.328A>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ile110Val (c.328A>G) in the general population?

SKI p.Ile110Val (c.328A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SKI p.Ile110Val (c.328A>G)?

AlphaMissense predicts likely benign (score 0.258) — an in-silico prediction, not a clinical call.

SKI p.Ile110Val

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.328A>G · rs2527577047 · VCV2496214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.258	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 289 bp · p 4.9e-08 · regional, not allelic
Overall
CADD	23.4	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 0.000254% European (non-Finnish) · 3/1,179,834 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,609,534 alleles · very rare exomes 3/1,457,432 · genomes 0/152,102 · 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.Ile110Val
Coding: c.328A>G
MANE Select: NM_003036
dbSNP: rs2527577047
Type: single nucleotide variant
Location: chr1:2229094 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 110: a β-strand

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.Ile110= 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
SKI p.Ala298Ser Uncertain significance ★★ ⚠ same condition
SKI p.Ala3Val 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-ile110val (accessed [today's date]).

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