Is MAPK3 p.Gly221= (c.663C>T) pathogenic?

MAPK3 p.Gly221= (c.663C>T) is classified Likely benign in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-16). Rare (popmax 0.105%, afr).

How common is MAPK3 p.Gly221= (c.663C>T) in the general population?

MAPK3 p.Gly221= (c.663C>T) is rare (popmax 0.105%, afr) (gnomAD).

MAPK3 p.Gly221=

c.663C>T · rs61764216 · VCV737233

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.13	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.46, phastCons 1
Overall
CADD	15.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% African / African-American · 79/74,976 alleles

Filtering AF 0.0866% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0797%

Overall 0.00521% 84/1,611,412 alleles · rare exomes 51/1,459,146 · genomes 33/152,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	949
Remaining individualsnot grpmax-eligible	0.00801%	12,483

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: MAPK3
Protein: p.Gly221=
Coding: c.663C>T
MANE Select: NM_002746
dbSNP: rs61764216
Type: single nucleotide variant
Location: chr16:30117782 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.09 · 8 PDB
Residue 221: the protein kinase domain

Full MAPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK3 p.Gly11= Likely benign ★★ same type
MAPK3 p.Pro336= Benign/Likely benign ★★ same type
MAPK3 p.Tyr148Cys Likely pathogenic ★ same type
MAPK3 p.Ala378Asp Uncertain significance ★ ⚠ same type
MAPK3 p.Arg15Ser Uncertain significance ★ ⚠ same type
MAPK3 p.Arg242Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gly 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/mapk3-p-gly221 (accessed [today's date]).

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