Is MAPK4 p.Arg195Cys (c.583C>T) pathogenic?

MAPK4 p.Arg195Cys (c.583C>T) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely benign (0.3266); Ultra-rare (popmax 0.0889%, sas).

How common is MAPK4 p.Arg195Cys (c.583C>T) in the general population?

MAPK4 p.Arg195Cys (c.583C>T) is ultra-rare (popmax 0.0889%, sas) (gnomAD).

What do computational predictors say about MAPK4 p.Arg195Cys (c.583C>T)?

AlphaMissense predicts likely benign (score 0.3266) — an in-silico prediction, not a clinical call.

MAPK4 p.Arg195Cys

c.583C>T · VCV3293224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3266 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0889%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3266	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -12.30	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -4.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 62 kb · p 0.00058 · regional, not allelic
Overall
CADD	24.1	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 0.0889% South Asian · 81/91,078 alleles

Filtering AF 0.0733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0675%

Overall 0.00719% 116/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0889%	1,124
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.005%	19,993
European (non-Finnish)	0.00195%	51,305
African / African-American	0.00133%	74,908

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.Arg195Cys
Coding: c.583C>T
MANE Select: NM_002747
Type: single nucleotide variant
Location: chr18:50715115 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04
Residue 195: the protein kinase domain

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

Similar variants

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.Arg198Leu Uncertain significance ★ ⚠ same type
MAPK4 p.Arg19His Uncertain significance ★ ⚠ same type
MAPK4 p.Arg272Ser 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-arg195cys (accessed [today's date]).

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