MLKL p.Ile405=
c.1215C>T · rs370078597 · VCV3203547
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.099%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.013 | strongly benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -2.1 | GERP -3.4 |
| Overall | ||
| CADD | 0.957 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.099%
Middle Eastern · 6/6,062 alleles
Filtering AF
0.0613%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0561%
Overall
0.0164%
264/1,614,032 alleles · ultra-rare
exomes 250/1,461,768 · genomes 14/152,264 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.099% | 1,010 |
| South Asian | 0.0758% | 1,320 |
| Remaining individualsnot grpmax-eligible | 0.0176% | 5,683 |
| European (non-Finnish) | 0.0141% | 7,109 |
| African / African-American | 0.012% | 8,339 |
| Admixed American | 0.00333% | 30,006 |
| East Asian | 0.00223% | 44,884 |
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
- MLKL
- Protein
- p.Ile405=
- Coding
- c.1215C>T
- MANE Select
- NM_152649
- dbSNP
- rs370078597
- Type
- single nucleotide variant
- Location
- chr16:74675380 (GRCh38)
- Gene constraint
- LOEUF 1.194 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 83.25 · 22 PDB
- Residue 405
- the protein kinase domain; an α-helix
Similar variants
- MLKL p.Asp100Glu Benign ★★ same type
- MLKL p.Leu294= Benign ★★ same type
- MLKL p.Lys234= Benign ★★ same type
- MLKL p.Ala406Thr Uncertain significance ★ ⚠ same type
- MLKL p.Ala450Val Uncertain significance ★ ⚠ same type
- MLKL p.Arg121Leu Uncertain significance ★ ⚠ same type
- MLKL p.Arg145Thr Uncertain significance ★ ⚠ same type
- MLKL p.Arg306Cys 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/mlkl-p-ile405 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown