Is SKI p.Pro35Ala (c.103C>G) pathogenic?

SKI p.Pro35Ala (c.103C>G) is classified Likely pathogenic in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely pathogenic (0.9865); Absent from gnomAD v4.1; Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro35Ala (c.103C>G)?

SKI p.Pro35Ala (c.103C>G) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Pro35Ala (c.103C>G) in the general population?

SKI p.Pro35Ala (c.103C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SKI p.Pro35Ala (c.103C>G)?

AlphaMissense predicts likely pathogenic (score 0.9865) — an in-silico prediction, not a clinical call.

SKI p.Pro35Ala

c.103C>G · rs397514590 · VCV1709127

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9865 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.9865	likely pathogenic ✓ concordant with ClinVar
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SKI
Protein: p.Pro35Ala
Coding: c.103C>G
MANE Select: NM_003036
dbSNP: rs397514590
Type: single nucleotide variant
Location: chr1:2228869 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 35: a UniProt-annotated variant site (in sgs); 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

Similar variants

SKI p.Pro35Ser Pathogenic ★★ ⚠ same residue
SKI p.Pro35= Likely benign ★★ same residue
SKI p.Pro35Gln Pathogenic ★ ⚠ same residue
SKI p.Pro35Leu Likely pathogenic ★ ⚠ same residue
SKI p.Pro35Arg Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro35ala (accessed [today's date]).

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