Is SKI p.Leu76Pro (c.227T>C) pathogenic?

SKI p.Leu76Pro (c.227T>C) is classified Conflicting classifications of pathogenicity in SKI (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-18). AlphaMissense: likely benign (0.1614); Ultra-rare (popmax 0.0683%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Leu76Pro (c.227T>C) in the general population?

SKI p.Leu76Pro (c.227T>C) is ultra-rare (popmax 0.0683%, afr) (gnomAD).

What do computational predictors say about SKI p.Leu76Pro (c.227T>C)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

SKI p.Leu76Pro

Q: What condition is associated with SKI p.Leu76Pro (c.227T>C)?

SKI p.Leu76Pro (c.227T>C) 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.227T>C · rs753070477 · VCV520167

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -4.50	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 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	25.7	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 0.0683% African / African-American · 50/73,210 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00348% 54/1,550,500 alleles · ultra-rare exomes 31/1,399,536 · genomes 23/150,964 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0683%	1,464
Admixed American	0.0019%	52,676
Remaining individualsnot grpmax-eligible	0.00166%	60,368
South Asian	0.00116%	85,882
European (non-Finnish)	8.66e-05%	1,155,191

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.Leu76Pro
Coding: c.227T>C
MANE Select: NM_003036
dbSNP: rs753070477
Type: single nucleotide variant
Location: chr1:2228993 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB

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.Leu76= 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-leu76pro (accessed [today's date]).

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