Is SKI p.Pro433Ser (c.1297C>T) pathogenic?

SKI p.Pro433Ser (c.1297C>T) is classified Benign/Likely benign in SKI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-29). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0352%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Pro433Ser (c.1297C>T)?

SKI p.Pro433Ser (c.1297C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Pro433Ser (c.1297C>T) in the general population?

SKI p.Pro433Ser (c.1297C>T) is ultra-rare (popmax 0.0352%, sas) (gnomAD).

What do computational predictors say about SKI p.Pro433Ser (c.1297C>T)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

SKI p.Pro433Ser

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.1297C>T · rs538775546 · VCV1769241

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP -0.36, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	14.98	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 0.0352% South Asian · 32/91,028 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00453% 73/1,611,954 alleles · ultra-rare exomes 58/1,459,664 · genomes 15/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0352%	2,845
Admixed American	0.0334%	2,998
Remaining individualsnot grpmax-eligible	0.0112%	8,910
European (non-Finnish)	0.00119%	84,261

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.Pro433Ser
Coding: c.1297C>T
MANE Select: NM_003036
dbSNP: rs538775546
Type: single nucleotide variant
Location: chr1:2303925 (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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SKI p.Pro433Leu Uncertain significance ★★ ⚠ same residue
SKI p.Pro433= Likely benign ★ same residue
SKI p.Pro433Arg Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro433ser (accessed [today's date]).

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