Is MAPK11 p.Asp176Glu (c.528C>G) pathogenic?

MAPK11 p.Asp176Glu (c.528C>G) is classified Uncertain significance in MAPK11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely benign (0.271); Very rare (popmax 0.00446%, eas).

How common is MAPK11 p.Asp176Glu (c.528C>G) in the general population?

MAPK11 p.Asp176Glu (c.528C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MAPK11 p.Asp176Glu (c.528C>G)?

AlphaMissense predicts likely benign (score 0.271) — an in-silico prediction, not a clinical call.

MAPK11 p.Asp176Glu

c.528C>G · VCV4051544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.271	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.6	GERP -3.4
Regional constraint	o/e 0.88	unconstrained · MANE · 5,341 bp · p 0.0083 · regional, not allelic
Overall
CADD	0.066	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00316% 51/1,612,358 alleles · very rare exomes 48/1,460,184 · genomes 3/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
European (non-Finnish)	0.0039%	25,648
Remaining individualsnot grpmax-eligible	0.0016%	62,452
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,076

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.Asp176Glu
Coding: c.528C>G
MANE Select: NM_002751
Type: single nucleotide variant
Location: chr22:50267016 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.88 · 4 PDB
Residue 176: 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-asp176glu (accessed [today's date]).

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