Is SKI p.Ser720Arg (c.2160C>G) pathogenic?

SKI p.Ser720Arg (c.2160C>G) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). AlphaMissense: likely benign (0.1055); Very rare (popmax 8.77e-05%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ser720Arg (c.2160C>G)?

SKI p.Ser720Arg (c.2160C>G) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Ser720Arg (c.2160C>G) in the general population?

SKI p.Ser720Arg (c.2160C>G) is very rare (popmax 8.77e-05%, nfe) (gnomAD).

What do computational predictors say about SKI p.Ser720Arg (c.2160C>G)?

AlphaMissense predicts likely benign (score 0.1055) — an in-silico prediction, not a clinical call.

SKI p.Ser720Arg

c.2160C>G · VCV3633457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.77e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.1055	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.8
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	0.38	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 8.77e-05% European (non-Finnish) · 1/1,140,236 alleles

Overall 6.54e-05% 1/1,528,896 alleles · very rare exomes 1/1,376,736 · genomes 0/152,160 · 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.Ser720Arg
Coding: c.2160C>G
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2306738 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 720: a modified residue (phosphoserine)

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.Ser720Asn 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-ser720arg (accessed [today's date]).

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