ENG p.Cys516Arg
c.1546T>C · VCV4904615
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
ambiguous
0.3724 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3724 | ambiguous |
|---|---|---|
| REVEL | 0.482 | indeterminate |
| SaProt | LLR -3.22 | tolerated |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.5 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 0.86 | unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic |
| Overall | ||
| CADD | 23.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- ENG
- Protein
- p.Cys516Arg
- Coding
- c.1546T>C
- MANE Select
- NM_001114753
- Type
- single nucleotide variant
- Location
- chr9:127818260 (GRCh38)
- Gene constraint
- LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.84 · 3 PDB
- Residue 516
- a disulfide bond; the zp domain
Similar variants
- ENG p.Cys516Ser Uncertain significance ★★ same residue
- ENG p.Cys516Gly Uncertain significance ★ ⚠ same residue
- ENG p.Cys516fs Likely pathogenic ★ same residue
- ENG p.Arg529His Pathogenic ★★★ same type
- ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same type
- ENG p.Cys382Tyr Pathogenic ★★★ same type
- ENG p.Cys549Gly Likely pathogenic ★★★ same type
- ENG p.Gly331Ser 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/eng-p-cys516arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown