Is SKI p.Pro72Ser (c.214C>T) pathogenic?

SKI p.Pro72Ser (c.214C>T) is classified Uncertain significance in SKI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0899); Very rare (popmax 0.00128%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SKI p.Pro72Ser (c.214C>T) in the general population?

SKI p.Pro72Ser (c.214C>T) is very rare (popmax 0.00128%, sas) (gnomAD).

What do computational predictors say about SKI p.Pro72Ser (c.214C>T)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

SKI p.Pro72Ser

Q: What condition is associated with SKI p.Pro72Ser (c.214C>T)?

SKI p.Pro72Ser (c.214C>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.214C>T · rs2527576481 · VCV2179453

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00128%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -7.76	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 7.3	GERP -0.41, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	25.1	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 0.00128% South Asian · 1/77,962 alleles

Filtering AF 8.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.7e-05%

Overall 0.000339% 5/1,475,812 alleles · very rare exomes 5/1,324,754 · genomes 0/151,058 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00128%	77,962
European (non-Finnish)	0.000358%	279,146

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.Pro72Ser
Coding: c.214C>T
MANE Select: NM_003036
dbSNP: rs2527576481
Type: single nucleotide variant
Location: chr1:2228980 (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.Pro72= 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-pro72ser (accessed [today's date]).

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