Is SKI p.Ala540Val (c.1619C>T) pathogenic?

SKI p.Ala540Val (c.1619C>T) is classified Conflicting classifications of pathogenicity in SKI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-16). AlphaMissense: likely benign (0.0941); Ultra-rare (popmax 0.0167%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Ala540Val (c.1619C>T) in the general population?

SKI p.Ala540Val (c.1619C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about SKI p.Ala540Val (c.1619C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

SKI p.Ala540Val

Q: What condition is associated with SKI p.Ala540Val (c.1619C>T)?

SKI p.Ala540Val (c.1619C>T) 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.1619C>T · rs764786977 · VCV213697

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.9, phastCons 0.92
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	24.2	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 0.0167% Middle Eastern · 1/6,002 alleles

Filtering AF 0.00537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00404% 63/1,560,528 alleles · ultra-rare exomes 57/1,408,200 · genomes 6/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,002
African / African-American	0.0109%	9,183
European (non-Finnish)	0.00451%	22,180
South Asian	0.00236%	42,403

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.Ala540Val
Coding: c.1619C>T
MANE Select: NM_003036
dbSNP: rs764786977
Type: single nucleotide variant
Location: chr1:2304437 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 540: 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.Ala540= Likely benign ★★ 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-ala540val (accessed [today's date]).

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