Is SKI p.Arg692Cys (c.2074C>T) pathogenic?

SKI p.Arg692Cys (c.2074C>T) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-17). AlphaMissense: likely pathogenic (0.8547); Very rare (popmax 0.000175%, nfe); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Arg692Cys (c.2074C>T)?

SKI p.Arg692Cys (c.2074C>T) is associated with Shprintzen-Goldberg syndrome (ClinVar).

How common is SKI p.Arg692Cys (c.2074C>T) in the general population?

SKI p.Arg692Cys (c.2074C>T) is very rare (popmax 0.000175%, nfe) (gnomAD).

What do computational predictors say about SKI p.Arg692Cys (c.2074C>T)?

AlphaMissense predicts likely pathogenic (score 0.8547) — an in-silico prediction, not a clinical call.

SKI p.Arg692Cys

c.2074C>T · rs1341756519 · VCV1470048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.8547	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -10.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000175% European (non-Finnish) · 2/1,145,220 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000194% 3/1,544,560 alleles · very rare exomes 2/1,392,470 · genomes 1/152,090 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00176%	56,824
European (non-Finnish)grpmax	0.000175%	572,610

Finnish 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.Arg692Cys
Coding: c.2074C>T
MANE Select: NM_003036
dbSNP: rs1341756519
Type: single nucleotide variant
Location: chr1:2306652 (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.Arg692= 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
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-arg692cys (accessed [today's date]).

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