Is SKI p.Arg645Pro (c.1934G>C) pathogenic?

SKI p.Arg645Pro (c.1934G>C) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.9438); Very rare (popmax 0.000257%, nfe).

How common is SKI p.Arg645Pro (c.1934G>C) in the general population?

SKI p.Arg645Pro (c.1934G>C) is very rare (popmax 0.000257%, nfe) (gnomAD).

What do computational predictors say about SKI p.Arg645Pro (c.1934G>C)?

AlphaMissense predicts likely pathogenic (score 0.9438) — an in-silico prediction, not a clinical call.

SKI p.Arg645Pro

c.1934G>C · VCV4974408

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9438	likely pathogenic
REVEL	0.723	pathogenic-leaning
SaProt	LLR -15.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	29.6	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 0.000257% European (non-Finnish) · 3/1,166,422 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000189% 3/1,584,572 alleles · very rare exomes 3/1,432,262 · genomes 0/152,310 · 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.Arg645Pro
Coding: c.1934G>C
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2306186 (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

Similar variants

SKI p.Arg645Gln Uncertain significance ★★ ⚠ same residue
SKI p.Arg645Leu Uncertain significance ★ ⚠ same residue
SKI p.Arg645= Likely benign ★ same residue
SKI p.Gly116Glu Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly117Arg Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly117Ser Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly34Cys Pathogenic ★★ ⚠ same type
SKI p.Gly34Ser Pathogenic/Likely pathogenic ★★ ⚠ same type

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-arg645pro (accessed [today's date]).

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