Is SKI p.Ala208Pro (c.622G>C) pathogenic?

SKI p.Ala208Pro (c.622G>C) is classified Uncertain significance in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0724); Very rare (popmax 0.00153%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ala208Pro (c.622G>C)?

SKI p.Ala208Pro (c.622G>C) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ala208Pro (c.622G>C) in the general population?

SKI p.Ala208Pro (c.622G>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about SKI p.Ala208Pro (c.622G>C)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

SKI p.Ala208Pro

c.622G>C · rs761138564 · VCV1015227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -5.45	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 7.4	GERP -2.1, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 97 bp · p 0.05 · regional, not allelic
Overall
CADD	23.0	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 0.00153% European (non-Finnish) · 18/1,176,124 alleles

Filtering AF 0.000956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000789%

Overall 0.00118% 19/1,605,232 alleles · very rare exomes 19/1,452,874 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,340
African / African-American	0.00134%	74,770

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.Ala208Pro
Coding: c.622G>C
MANE Select: NM_003036
dbSNP: rs761138564
Type: single nucleotide variant
Location: chr1:2229388 (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.Ala208Val Uncertain significance ★★ ⚠ same residue
SKI p.Ala208= 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

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-ala208pro (accessed [today's date]).

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