Is SKI p.Ala46Asp (c.137C>A) pathogenic?

SKI p.Ala46Asp (c.137C>A) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely benign (0.3101); Very rare (popmax 9.25e-05%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ala46Asp (c.137C>A)?

SKI p.Ala46Asp (c.137C>A) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Ala46Asp (c.137C>A) in the general population?

SKI p.Ala46Asp (c.137C>A) is very rare (popmax 9.25e-05%, nfe) (gnomAD).

What do computational predictors say about SKI p.Ala46Asp (c.137C>A)?

AlphaMissense predicts likely benign (score 0.3101) — an in-silico prediction, not a clinical call.

SKI p.Ala46Asp

c.137C>A · VCV4685834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.25e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.3101	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -7.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP -0.79, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 9.25e-05% European (non-Finnish) · 1/1,080,920 alleles

Overall 7.05e-05% 1/1,417,506 alleles · very rare exomes 1/1,267,542 · genomes 0/149,964 · joint denominator

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.Ala46Asp
Coding: c.137C>A
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2228903 (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.Ala46Val Uncertain significance ★ ⚠ same residue
SKI p.Ala46= Likely benign ★ same residue
SKI p.Ala46Gly Uncertain significance ★★ ⚠ same residue
SKI p.Ala46Ser Uncertain significance ★ ⚠ same residue
SKI p.Ala46Thr 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

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-ala46asp (accessed [today's date]).

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