Is MLKL p.Leu320Arg (c.959T>G) pathogenic?

MLKL p.Leu320Arg (c.959T>G) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.6517); Ultra-rare (popmax 0.0986%, afr).

How common is MLKL p.Leu320Arg (c.959T>G) in the general population?

MLKL p.Leu320Arg (c.959T>G) is ultra-rare (popmax 0.0986%, afr) (gnomAD).

What do computational predictors say about MLKL p.Leu320Arg (c.959T>G)?

AlphaMissense predicts likely pathogenic (score 0.6517) — an in-silico prediction, not a clinical call.

MLKL p.Leu320Arg

c.959T>G · VCV4108708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6517	likely pathogenic · top 10% in MLKL
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -14.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.0986% African / African-American · 74/75,014 alleles

Filtering AF 0.0805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0739%

Overall 0.00545% 88/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0986%	1,014
Admixed American	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	8.48e-05%	1,179,711

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.Leu320Arg
Coding: c.959T>G
MANE Select: NM_152649
Type: single nucleotide variant
Location: chr16:74678978 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 320: the protein kinase domain; 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-leu320arg (accessed [today's date]).

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