Is SKI p.His25= (c.75C>T) pathogenic?

SKI p.His25= (c.75C>T) is classified Likely benign in SKI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Very rare (popmax 0.00486%, amr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.His25= (c.75C>T)?

SKI p.His25= (c.75C>T) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.His25= (c.75C>T) in the general population?

SKI p.His25= (c.75C>T) is very rare (popmax 0.00486%, amr) (gnomAD).

SKI p.His25=

c.75C>T · rs1486448334 · VCV511227

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00486%, amr)

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.22	GERP -2.2, phastCons 0.86
Overall
CADD	10.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00486% Admixed American · 2/41,154 alleles

Filtering AF 0.000805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000301%

Overall 0.000775% 11/1,419,630 alleles · very rare exomes 9/1,270,118 · genomes 2/149,512 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00486%	20,577
Remaining individualsnot grpmax-eligible	0.00379%	26,353
Finnishnot grpmax-eligible	0.00246%	40,676
European (non-Finnish)	0.000555%	180,296

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.His25=
Coding: c.75C>T
MANE Select: NM_003036
dbSNP: rs1486448334
Type: single nucleotide variant
Location: chr1:2228841 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 25: an α-helix

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.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
SKI p.Pro35Ser 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-his25 (accessed [today's date]).

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