Is MLKL p.Arg428Trp (c.1282C>T) pathogenic?

MLKL p.Arg428Trp (c.1282C>T) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1439); Very rare (popmax 0.00398%, nfe).

How common is MLKL p.Arg428Trp (c.1282C>T) in the general population?

MLKL p.Arg428Trp (c.1282C>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about MLKL p.Arg428Trp (c.1282C>T)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

MLKL p.Arg428Trp

c.1282C>T · VCV4108710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1439	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -0.54
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	18.82	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

Grpmax group 0.00398% European (non-Finnish) · 47/1,180,020 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00304% 49/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,107
African / African-American	0.00267%	37,451

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.Arg428Trp
Coding: c.1282C>T
MANE Select: NM_152649
Type: single nucleotide variant
Location: chr16:74675059 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 428: the protein kinase domain

Full MLKL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MLKL p.Arg428Gly Uncertain significance ★ ⚠ same residue
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

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-arg428trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown