Is SKI p.Arg595His (c.1784G>A) pathogenic?

SKI p.Arg595His (c.1784G>A) is classified Uncertain significance in SKI (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-10). AlphaMissense: likely pathogenic (0.5682); Very rare (popmax 0.000428%, nfe); Associated with SKI-related disorder.

What condition is associated with SKI p.Arg595His (c.1784G>A)?

SKI p.Arg595His (c.1784G>A) is associated with SKI-related disorder (ClinVar).

How common is SKI p.Arg595His (c.1784G>A) in the general population?

SKI p.Arg595His (c.1784G>A) is very rare (popmax 0.000428%, nfe) (gnomAD).

What do computational predictors say about SKI p.Arg595His (c.1784G>A)?

AlphaMissense predicts likely pathogenic (score 0.5682) — an in-silico prediction, not a clinical call.

SKI p.Arg595His

c.1784G>A · rs2521511133 · VCV3033674

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000428%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

SKI-related disorder

Computational evidence

Protein change
AlphaMissense	0.5682	likely pathogenic
REVEL	0.601	indeterminate
SaProt	LLR -10.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	29.5	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 0.000428% European (non-Finnish) · 5/1,168,696 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000315% 5/1,587,380 alleles · very rare exomes 5/1,435,022 · genomes 0/152,358 · 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.Arg595His
Coding: c.1784G>A
MANE Select: NM_003036
dbSNP: rs2521511133
Type: single nucleotide variant
Location: chr1:2306036 (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

SKI-related disorder

Similar variants

SKI p.Arg595= Likely benign ★★ same residue
SKI p.Arg595Cys Uncertain significance ★ ⚠ same residue
SKI p.Arg595Leu Uncertain significance ★ ⚠ same residue
SKI p.Ser27Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
SKI p.Arg373Cys Uncertain significance ★★ ⚠ same condition
SKI p.Pro715Ser Uncertain significance ★★ ⚠ same condition
SKI p.Pro728Ala Uncertain significance ★★ ⚠ same condition
SKI p.Arg319Gly Uncertain significance ★ ⚠ 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-arg595his (accessed [today's date]).

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