Is SKI p.Pro256Leu (c.767C>T) pathogenic?

SKI p.Pro256Leu (c.767C>T) is classified Uncertain significance in SKI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-12). AlphaMissense: likely pathogenic (0.8397); Absent from gnomAD v4.1; Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Pro256Leu (c.767C>T)?

SKI p.Pro256Leu (c.767C>T) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Pro256Leu (c.767C>T) in the general population?

SKI p.Pro256Leu (c.767C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SKI p.Pro256Leu (c.767C>T)?

AlphaMissense predicts likely pathogenic (score 0.8397) — an in-silico prediction, not a clinical call.

SKI p.Pro256Leu

c.767C>T · rs2100790888 · VCV1377383

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8397 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.8397	likely pathogenic
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -12.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 220 bp · p 6e-08 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Pro256Leu
Coding: c.767C>T
MANE Select: NM_003036
dbSNP: rs2100790888
Type: single nucleotide variant
Location: chr1:2229533 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 256: 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.Pro256= 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
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-pro256leu (accessed [today's date]).

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