SPEN p.Arg754=
c.2262G>A · VCV4533787
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1.1 | GERP -3, phastCons 1 |
| Overall | ||
| CADD | 8.405 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,084 alleles
Filtering AF
0.00106%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000495%
Overall
0.000805%
13/1,614,002 alleles · ultra-rare
exomes 11/1,461,882 · genomes 2/152,120 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,084 |
| African / African-American | 0.004% | 24,970 |
| Admixed American | 0.00167% | 59,990 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,486 |
| European (non-Finnish) | 0.000593% | 168,576 |
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
- SPEN
- Protein
- p.Arg754=
- Coding
- c.2262G>A
- MANE Select
- NM_015001
- Type
- single nucleotide variant
- Location
- chr1:15928502 (GRCh38)
- Gene constraint
- LOEUF 0.094 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Residue 754
- the 'disordered' region; a UniProt-annotated variant site (in ratars)
Similar variants
- SPEN p.Arg1170Ter Pathogenic ★★ same type
- SPEN p.Arg1241Ter Pathogenic ★★ same type
- SPEN p.Arg1265Ter Pathogenic ★★ same type
- SPEN p.Arg2337Ter Likely pathogenic ★★ same type
- SPEN p.Arg2342Ter Pathogenic ★★ same type
- SPEN p.Arg308Ter Pathogenic ★★ same type
- SPEN p.Arg3168Ter Pathogenic/Likely pathogenic ★★ same type
- SPEN p.Arg535Ter 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/spen-p-arg754 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown