Is MAPK4 p.Ser521Ala (c.1561T>G) pathogenic?

MAPK4 p.Ser521Ala (c.1561T>G) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-20). AlphaMissense: likely benign (0.0581); Ultra-rare (popmax 0.0261%, nfe).

How common is MAPK4 p.Ser521Ala (c.1561T>G) in the general population?

MAPK4 p.Ser521Ala (c.1561T>G) is ultra-rare (popmax 0.0261%, nfe) (gnomAD).

What do computational predictors say about MAPK4 p.Ser521Ala (c.1561T>G)?

AlphaMissense predicts likely benign (score 0.0581) — an in-silico prediction, not a clinical call.

MAPK4 p.Ser521Ala

c.1561T>G · VCV3293223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0581 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0261%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0581	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -6.30	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 0.85	GERP -2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 3,740 bp · p 0.94 · regional, not allelic
Overall
CADD	12.9	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 0.0261% European (non-Finnish) · 294/1,127,280 alleles

Filtering AF 0.0236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0227%

Overall 0.026% 393/1,511,278 alleles · ultra-rare exomes 358/1,359,362 · genomes 35/151,916 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.153%	654
European (non-Finnish)grpmax	0.0261%	3,834
Remaining individualsnot grpmax-eligible	0.0155%	6,452
African / African-American	0.00284%	35,230

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser521Ala
Coding: c.1561T>G
MANE Select: NM_002747
Type: single nucleotide variant
Location: chr18:50729651 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04
Residue 521: the 'disordered' region

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

Similar variants

MAPK4 p.Ser521Leu 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
MAPK4 p.Arg198Leu 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-ser521ala (accessed [today's date]).

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