Is MLKL p.Lys99Arg (c.296A>G) pathogenic?

MLKL p.Lys99Arg (c.296A>G) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0744); Absent from gnomAD v4.1.

How common is MLKL p.Lys99Arg (c.296A>G) in the general population?

MLKL p.Lys99Arg (c.296A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLKL p.Lys99Arg (c.296A>G)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

MLKL p.Lys99Arg

c.296A>G · VCV4552152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -5.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.9	GERP -4.7
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	0.029	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: MLKL
Protein: p.Lys99Arg
Coding: c.296A>G
MANE Select: NM_152649
Type: single nucleotide variant
Location: chr16:74695462 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 99: the 'n-terminal bundle and brace (nbb); mediates insp6 binding' region; an α-helix

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

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-lys99arg (accessed [today's date]).

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