Is SKI p.Ser241Arg (c.723C>G) pathogenic?

SKI p.Ser241Arg (c.723C>G) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-12). AlphaMissense: likely pathogenic (0.6909); Very rare (popmax 0.0011%, sas); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ser241Arg (c.723C>G)?

SKI p.Ser241Arg (c.723C>G) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Ser241Arg (c.723C>G) in the general population?

SKI p.Ser241Arg (c.723C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SKI p.Ser241Arg (c.723C>G)?

AlphaMissense predicts likely pathogenic (score 0.6909) — an in-silico prediction, not a clinical call.

SKI p.Ser241Arg

c.723C>G · rs2100790799 · VCV1055588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.6909	likely pathogenic
REVEL	0.397	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -3.9, phastCons 0.006
Regional constraint	o/e 0.47	unconstrained · MANE · 220 bp · p 6e-08 · regional, not allelic
Overall
CADD	21.1	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 0.0011% South Asian · 1/91,068 alleles

Overall 6.2e-05% 1/1,611,622 alleles · very rare exomes 1/1,459,266 · genomes 0/152,356 · 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.Ser241Arg
Coding: c.723C>G
MANE Select: NM_003036
dbSNP: rs2100790799
Type: single nucleotide variant
Location: chr1:2229489 (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.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
SKI p.Pro35Ser 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-ser241arg (accessed [today's date]).

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