Is SKI p.Ala55Pro (c.163G>C) pathogenic?

SKI p.Ala55Pro (c.163G>C) is classified Conflicting classifications of pathogenicity in SKI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-12). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0102%, eas); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ala55Pro (c.163G>C)?

SKI p.Ala55Pro (c.163G>C) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ala55Pro (c.163G>C) in the general population?

SKI p.Ala55Pro (c.163G>C) is ultra-rare (popmax 0.0102%, eas) (gnomAD).

What do computational predictors say about SKI p.Ala55Pro (c.163G>C)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

SKI p.Ala55Pro

c.163G>C · rs769506718 · VCV978540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -6.46	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 5.4	GERP 0.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	23.6	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 0.0102% East Asian · 3/29,322 alleles

Filtering AF 0.00271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00145%

Overall 0.000433% 6/1,384,866 alleles · ultra-rare exomes 4/1,234,986 · genomes 2/149,880 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0102%	9,774
Remaining individualsnot grpmax-eligible	0.00393%	25,457
European (non-Finnish)	9.39e-05%	1,064,631

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.Ala55Pro
Coding: c.163G>C
MANE Select: NM_003036
dbSNP: rs769506718
Type: single nucleotide variant
Location: chr1:2228929 (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

Shprintzen-Goldberg syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

SKI p.Ala55Thr Uncertain significance ★★ ⚠ same residue
SKI p.Ala55Val Uncertain significance ★ ⚠ same residue
SKI p.Ala55= Likely benign ★ same residue
SKI p.Ala55Glu 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

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-ala55pro (accessed [today's date]).

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