CISH p.Leu223=
c.669G>A · rs76541284 · VCV716306
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
low-frequency (popmax 2.32%, afr)
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 -0.14 | GERP -3.7, phastCons 0.58 |
| Overall | ||
| CADD | 6.213 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
2.32%
African / African-American · 1,738/75,042 alleles
Filtering AF
2.23%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 2.19%
Overall
0.128%
2,064/1,613,888 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 2.32% | 43 |
| Admixed American | 0.235% | 426 |
| Remaining individualsnot grpmax-eligible | 0.216% | 463 |
| Middle Eastern | 0.132% | 758 |
| South Asian | 0.00439% | 22,773 |
| European (non-Finnish) | 0.00322% | 31,051 |
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
- CISH
- Protein
- p.Leu223=
- Coding
- c.669G>A
- MANE Select
- NM_145071
- dbSNP
- rs76541284
- Type
- single nucleotide variant
- Location
- chr3:50607715 (GRCh38)
- Gene constraint
- LOEUF 0.956 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 73.91
- Residue 223
- the socs box domain
Similar variants
- CISH p.Arg78Gln Likely benign ★★ same type
- CISH p.Ser173= Benign/Likely benign ★★ same type
- CISH c.20+1222A>G Uncertain significance ★ same type
- CISH c.20+1236G>A Uncertain significance ★ same type
- CISH c.20+1246C>A Uncertain significance ★ same type
- CISH p.Arg107His Uncertain significance ★ ⚠ same type
- CISH p.Arg130Cys Uncertain significance ★ ⚠ same type
- CISH p.Arg139His 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/cish-p-leu223 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown