Is MLKL p.His451Arg (c.1352A>G) pathogenic?

MLKL p.His451Arg (c.1352A>G) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-30). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00133%, afr).

How common is MLKL p.His451Arg (c.1352A>G) in the general population?

MLKL p.His451Arg (c.1352A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MLKL p.His451Arg (c.1352A>G)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

MLKL p.His451Arg

c.1352A>G · rs1959494506 · VCV2609092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -10.74	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 0.47	GERP 1.7, phastCons 0.001
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	13.31	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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,054 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
European (non-Finnish)	0.000169%	590,019

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.His451Arg
Coding: c.1352A>G
MANE Select: NM_152649
dbSNP: rs1959494506
Type: single nucleotide variant
Location: chr16:74674989 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 451: the protein kinase domain

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

Similar variants

MLKL p.His451Tyr Likely benign ★ 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-his451arg (accessed [today's date]).

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