Is MAPK11 p.Phe99Leu (c.297C>A) pathogenic?

MAPK11 p.Phe99Leu (c.297C>A) is classified Uncertain significance in MAPK11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.9511); Very rare (popmax 0.00209%, nfe).

How common is MAPK11 p.Phe99Leu (c.297C>A) in the general population?

MAPK11 p.Phe99Leu (c.297C>A) is very rare (popmax 0.00209%, nfe) (gnomAD).

What do computational predictors say about MAPK11 p.Phe99Leu (c.297C>A)?

AlphaMissense predicts likely pathogenic (score 0.9511) — an in-silico prediction, not a clinical call.

MAPK11 p.Phe99Leu

c.297C>A · VCV4103725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00209%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9511	likely pathogenic
REVEL	0.292	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.55, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,341 bp · p 0.0083 · regional, not allelic
Overall
CADD	27.5	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 0.00209% European (non-Finnish) · 24/1,145,790 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00162% 25/1,547,654 alleles · very rare exomes 25/1,395,482 · genomes 0/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00209%	47,741
Admixed American	0.00196%	51,078

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: MAPK11
Protein: p.Phe99Leu
Coding: c.297C>A
MANE Select: NM_002751
Type: single nucleotide variant
Location: chr22:50267577 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.88 · 4 PDB
Residue 99: the protein kinase domain

Full MAPK11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK11 c.611-7C>T Benign ★★ same type
MAPK11 p.Ala121Ser Uncertain significance ★ ⚠ same type
MAPK11 p.Ala184Thr Uncertain significance ★ ⚠ same type
MAPK11 p.Ala304Ser Uncertain significance ★ ⚠ same type
MAPK11 p.Arg189Gln Uncertain significance ★ ⚠ same type
MAPK11 p.Arg332His Uncertain significance ★ ⚠ same type
MAPK11 p.Arg45Trp Uncertain significance ★ ⚠ same type
MAPK11 p.Asp161Asn 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/mapk11-p-phe99leu (accessed [today's date]).

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