Is MLKL p.Met1Val (c.1A>G) pathogenic?

MLKL p.Met1Val (c.1A>G) is classified Benign in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Rare (popmax 0.753%, nfe).

How common is MLKL p.Met1Val (c.1A>G) in the general population?

MLKL p.Met1Val (c.1A>G) is rare (popmax 0.753%, nfe) (gnomAD).

MLKL p.Met1Val

c.1A>G · rs33972728 · VCV770791

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.753%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.406	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.1, phastCons 1
Overall
CADD	17.74	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.753% European (non-Finnish) · 8,751/1,162,786 alleles

Filtering AF 0.739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.734%

Overall 0.694% 10,975/1,580,872 alleles · rare exomes 10,088/1,428,546 · genomes 887/152,326 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.65%	38
European (non-Finnish)grpmax	0.753%	133
Remaining individualsnot grpmax-eligible	0.636%	157
Admixed American	0.151%	663
Middle Eastern	0.136%	738
African / African-American	0.118%	847
Ashkenazi Jewishnot grpmax-eligible	0.0107%	9,349
South Asian	0.00343%	29,181
East Asian	0.00225%	44,418

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met1Val
Coding: c.1A>G
MANE Select: NM_152649
dbSNP: rs33972728
Type: single nucleotide variant
Location: chr16:74695757 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 1: the 'n-terminal bundle and brace (nbb); mediates insp6 binding' region

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-met1val (accessed [today's date]).

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