Is MAPK4 p.Pro522Ser (c.1564C>T) pathogenic?

MAPK4 p.Pro522Ser (c.1564C>T) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.065); Very rare (popmax 0.00565%, afr).

How common is MAPK4 p.Pro522Ser (c.1564C>T) in the general population?

MAPK4 p.Pro522Ser (c.1564C>T) is very rare (popmax 0.00565%, afr) (gnomAD).

What do computational predictors say about MAPK4 p.Pro522Ser (c.1564C>T)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

MAPK4 p.Pro522Ser

c.1564C>T · VCV3293230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00565%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.56, phastCons 0.69
Regional constraint	o/e 1.00	unconstrained · MANE · 3,740 bp · p 0.94 · regional, not allelic
Overall
CADD	16.74	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 0.00565% African / African-American · 4/70,826 alleles

Filtering AF 0.00192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.000395% 6/1,518,038 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00565%	17,707
Remaining individualsnot grpmax-eligible	0.00171%	58,430
South Asian	0.00126%	79,288

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: MAPK4
Protein: p.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_002747
Type: single nucleotide variant
Location: chr18:50729654 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04
Residue 522: the 'disordered' region

Full MAPK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK4 p.Pro522Ala Uncertain significance ★ ⚠ same residue
MAPK4 p.Pro522Leu Uncertain significance ★ ⚠ same residue
MAPK4 p.Ala2Ser Uncertain significance ★ ⚠ same type
MAPK4 p.Ala473Val Uncertain significance ★ ⚠ same type
MAPK4 p.Ala481Gly Uncertain significance ★ ⚠ same type
MAPK4 p.Ala487Asp Uncertain significance ★ ⚠ same type
MAPK4 p.Ala9Ser Uncertain significance ★ ⚠ same type
MAPK4 p.Arg195Cys 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/mapk4-p-pro522ser (accessed [today's date]).

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