Is SKI p.Ile332Val (c.994A>G) pathogenic?

SKI p.Ile332Val (c.994A>G) is classified Benign/Likely benign in SKI (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0584); Rare (popmax 0.355%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Ile332Val (c.994A>G) in the general population?

SKI p.Ile332Val (c.994A>G) is rare (popmax 0.355%, sas) (gnomAD).

What do computational predictors say about SKI p.Ile332Val (c.994A>G)?

AlphaMissense predicts likely benign (score 0.0584) — an in-silico prediction, not a clinical call.

SKI p.Ile332Val

Q: What condition is associated with SKI p.Ile332Val (c.994A>G)?

SKI p.Ile332Val (c.994A>G) is associated with familial thoracic aortic aneurysm and aortic dissection, Shprintzen-Goldberg syndrome (ClinVar).

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.994A>G · rs374264201 · VCV513013

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0584 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.355%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0584	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -4.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -3.8, phastCons 0.001
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	5.099	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 0.355% South Asian · 323/91,086 alleles

Filtering AF 0.323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.31%

Overall 0.0283% 456/1,613,682 alleles · rare exomes 433/1,461,360 · genomes 23/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.355%	282
Middle Eastern	0.313%	319
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed American	0.0117%	8,576
European (non-Finnish)	0.00754%	13,259
African / African-American	0.00133%	75,064

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.Ile332Val
Coding: c.994A>G
MANE Select: NM_003036
dbSNP: rs374264201
Type: single nucleotide variant
Location: chr1:2303002 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 332: 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

Also linked: Shprintzen-Goldberg syndrome

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SKI p.Ile332Leu Uncertain significance ★ ⚠ same residue
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

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-ile332val (accessed [today's date]).

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