Is MLKL p.Pro205Leu (c.614C>T) pathogenic?

MLKL p.Pro205Leu (c.614C>T) is classified Uncertain significance in MLKL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.1282); Ultra-rare (popmax 0.0187%, afr).

How common is MLKL p.Pro205Leu (c.614C>T) in the general population?

MLKL p.Pro205Leu (c.614C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about MLKL p.Pro205Leu (c.614C>T)?

AlphaMissense predicts likely benign (score 0.1282) — an in-silico prediction, not a clinical call.

MLKL p.Pro205Leu

c.614C>T · rs767152998 · VCV2406568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1282 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1282	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.15, phastCons 0.34
Regional constraint	o/e 1.21	unconstrained · MANE · 23 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	19.51	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 0.0187% African / African-American · 14/74,970 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00273% 44/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,355
Remaining individualsnot grpmax-eligible	0.0048%	20,834
East Asian	0.00223%	44,868
South Asian	0.0022%	45,537
European (non-Finnish)	0.00186%	53,637
Admixed American	0.00167%	59,994
Finnishnot grpmax-eligible	0.00156%	63,996

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.Pro205Leu
Coding: c.614C>T
MANE Select: NM_152649
dbSNP: rs767152998
Type: single nucleotide variant
Location: chr16:74691385 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 22 PDB
Residue 205: the protein kinase domain

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-pro205leu (accessed [today's date]).

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