Is MAPK1 p.Leu264= (c.790T>C) pathogenic?

MAPK1 p.Leu264= (c.790T>C) is classified Likely benign in MAPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-01). Ultra-rare (popmax 0.0189%, nfe).

How common is MAPK1 p.Leu264= (c.790T>C) in the general population?

MAPK1 p.Leu264= (c.790T>C) is ultra-rare (popmax 0.0189%, nfe) (gnomAD).

MAPK1 p.Leu264=

c.790T>C · rs141683377 · VCV2672898

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0189%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 0.73, phastCons 0.99
Overall
CADD	9.152	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0189% European (non-Finnish) · 223/1,178,594 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0161%

Overall 0.015% 242/1,611,698 alleles · ultra-rare exomes 232/1,459,358 · genomes 10/152,340 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0304%	3,285
European (non-Finnish)grpmax	0.0189%	5,285

Remaining individuals 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: MAPK1
Protein: p.Leu264=
Coding: c.790T>C
MANE Select: NM_002745
dbSNP: rs141683377
Type: single nucleotide variant
Location: chr22:21788323 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.99 · 157 PDB
Residue 264: the protein kinase domain; a DNA-binding region; an α-helix

Full MAPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK1 p.Ala174Val Pathogenic ★★ ⚠ same type
MAPK1 p.Arg135Thr Likely pathogenic ★★ same type
MAPK1 p.Asp318Asn Pathogenic/Likely pathogenic ★★ same type
MAPK1 p.Asp318Gly Pathogenic ★★ same type
MAPK1 p.Glu322Gln Pathogenic/Likely pathogenic ★★ same type
MAPK1 p.His80Tyr Pathogenic ★★ same type
MAPK1 p.Asn27Asp Uncertain significance ★★ ⚠ same type
MAPK1 p.Ala325= Likely benign ★★ 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/mapk1-p-leu264 (accessed [today's date]).

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