Is SKI p.Arg648Gln (c.1943G>A) pathogenic?

SKI p.Arg648Gln (c.1943G>A) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely benign (0.2011); Very rare (popmax 8.58e-05%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Arg648Gln (c.1943G>A)?

SKI p.Arg648Gln (c.1943G>A) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Arg648Gln (c.1943G>A) in the general population?

SKI p.Arg648Gln (c.1943G>A) is very rare (popmax 8.58e-05%, nfe) (gnomAD).

What do computational predictors say about SKI p.Arg648Gln (c.1943G>A)?

AlphaMissense predicts likely benign (score 0.2011) — an in-silico prediction, not a clinical call.

SKI p.Arg648Gln

c.1943G>A · VCV3715680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.58e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.2011	likely benign
REVEL	0.615	indeterminate
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.74	donor gain · deltas
Pangolin	Δ0.25	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	34.0	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 8.58e-05% European (non-Finnish) · 1/1,165,802 alleles

Overall 0.000126% 2/1,583,216 alleles · very rare exomes 1/1,431,016 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00163%	61,356
European (non-Finnish)grpmax	8.58e-05%	1,165,801

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg648Gln
Coding: c.1943G>A
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2306195 (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.Arg648Gly Uncertain significance ★★ ⚠ same residue
SKI p.Arg648= Likely benign ★★ same residue
SKI p.Arg648Pro 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

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-arg648gln (accessed [today's date]).

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