Is SKI p.Pro196Ser (c.586C>T) pathogenic?

SKI p.Pro196Ser (c.586C>T) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.2734); Very rare (popmax 0.00345%, amr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro196Ser (c.586C>T)?

SKI p.Pro196Ser (c.586C>T) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Pro196Ser (c.586C>T) in the general population?

SKI p.Pro196Ser (c.586C>T) is very rare (popmax 0.00345%, amr) (gnomAD).

What do computational predictors say about SKI p.Pro196Ser (c.586C>T)?

AlphaMissense predicts likely benign (score 0.2734) — an in-silico prediction, not a clinical call.

SKI p.Pro196Ser

c.586C>T · VCV3668538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00345%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.2734	likely benign
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -2.7, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 97 bp · p 0.05 · regional, not allelic
Overall
CADD	29.5	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 0.00345% Admixed American · 2/57,920 alleles

Filtering AF 0.000573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.000188% 3/1,596,194 alleles · very rare exomes 2/1,443,940 · genomes 1/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00345%	28,960
European (non-Finnish)	8.53e-05%	1,171,756

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.Pro196Ser
Coding: c.586C>T
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2229352 (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

Similar variants

SKI p.Pro196Leu 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
SKI p.Gly34Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
SKI p.Gly34Val Pathogenic ★★ ⚠ same condition
SKI p.Leu32Val 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-pro196ser (accessed [today's date]).

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