Is SKI p.Arg489Lys (c.1466G>A) pathogenic?

SKI p.Arg489Lys (c.1466G>A) is classified Likely benign in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.17); Ultra-rare (popmax 0.015%, amr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Arg489Lys (c.1466G>A)?

SKI p.Arg489Lys (c.1466G>A) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Arg489Lys (c.1466G>A) in the general population?

SKI p.Arg489Lys (c.1466G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about SKI p.Arg489Lys (c.1466G>A)?

AlphaMissense predicts likely benign (score 0.17) — an in-silico prediction, not a clinical call.

SKI p.Arg489Lys

c.1466G>A · VCV3669678

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.17 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.17	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	22.3	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 0.015% Admixed American · 9/59,992 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000992% 16/1,612,560 alleles · ultra-rare exomes 5/1,460,252 · genomes 11/152,308 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
African / African-American	0.00933%	10,717

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.Arg489Lys
Coding: c.1466G>A
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2304094 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 489: the 'disordered' region

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.Arg489Ser Uncertain significance ★ ⚠ same residue
SKI p.Arg489= 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

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-arg489lys (accessed [today's date]).

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