Is MLKL p.Phe232Leu (c.696C>A) pathogenic?

MLKL p.Phe232Leu (c.696C>A) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely pathogenic (0.8674); Very rare (popmax 0.00221%, sas).

How common is MLKL p.Phe232Leu (c.696C>A) in the general population?

MLKL p.Phe232Leu (c.696C>A) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about MLKL p.Phe232Leu (c.696C>A)?

AlphaMissense predicts likely pathogenic (score 0.8674) — an in-silico prediction, not a clinical call.

MLKL p.Phe232Leu

c.696C>A · rs749275387 · VCV2295312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8674	likely pathogenic · top 3% in MLKL
REVEL	0.56	indeterminate
SaProt	LLR -4.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	19.11	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 0.00221% South Asian · 2/90,528 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,610,132 alleles · very rare exomes 3/1,457,972 · genomes 0/152,160 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,264
Remaining individualsnot grpmax-eligible	0.00161%	62,298

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.Phe232Leu
Coding: c.696C>A
MANE Select: NM_152649
dbSNP: rs749275387
Type: single nucleotide variant
Location: chr16:74691303 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 232: the protein kinase domain; a β-strand

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-phe232leu (accessed [today's date]).

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