Is SKI p.Pro35Gln (c.104C>A) pathogenic?

SKI p.Pro35Gln (c.104C>A) is classified Pathogenic in SKI (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9982); No allele count reported in gnomAD v4.1 (AN 1,430,318); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro35Gln (c.104C>A)?

SKI p.Pro35Gln (c.104C>A) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Pro35Gln (c.104C>A) in the general population?

SKI p.Pro35Gln (c.104C>A) is no allele count reported in gnomAD v4.1 (AN 1,430,318) (gnomAD).

What do computational predictors say about SKI p.Pro35Gln (c.104C>A)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

SKI p.Pro35Gln

c.104C>A · rs397514589 · VCV39785

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,430,318)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic ✓ concordant with ClinVar · top 5% in SKI
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	26.2	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

No allele count reported in gnomAD v4.1 (AN 1,430,318). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SKI
Protein: p.Pro35Gln
Coding: c.104C>A
MANE Select: NM_003036
dbSNP: rs397514589
Type: single nucleotide variant
Location: chr1:2228870 (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.Pro35Ala Likely 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-pro35gln (accessed [today's date]).

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