SPEG p.Arg593=
c.1777C>A · rs762541538 · VCV2896709
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00667%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1.6 | GERP 1.4, phastCons 0.54 |
| Overall | ||
| CADD | 13.08 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00667%
Admixed American · 3/44,950 alleles
Filtering AF
0.00177%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000891%
Overall
0.00147%
22/1,493,768 alleles · very rare
exomes 20/1,341,706 · genomes 2/152,062 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00667% | 14,983 |
| Remaining individualsnot grpmax-eligible | 0.00173% | 57,872 |
| European (non-Finnish) | 0.0016% | 62,593 |
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
- SPEG
- Protein
- p.Arg593=
- Coding
- c.1777C>A
- MANE Select
- NM_005876
- dbSNP
- rs762541538
- Type
- single nucleotide variant
- Location
- chr2:219448935 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI <0.01 (gnomAD)
- Residue 593
- the 'disordered' region
Similar variants
- SPEG p.Arg1467Ter Likely pathogenic ★★ same type
- SPEG p.Ser131Ter Pathogenic/Likely pathogenic ★★ same type
- SPEG c.3301+5G>A Uncertain significance ★★ same type
- SPEG c.478+5G>A Uncertain significance ★★ same type
- SPEG p.Ala121Thr Uncertain significance ★★ same type
- SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same type
- SPEG p.Ala1334Val Uncertain significance ★★ ⚠ same type
- SPEG p.Ala154Asp Uncertain significance ★★ ⚠ 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/speg-p-arg593 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown