Is MAPK1 p.Pro323Arg (c.968C>G) pathogenic?

MAPK1 p.Pro323Arg (c.968C>G) is classified Pathogenic in MAPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-01). AlphaMissense: likely pathogenic (0.9504); Absent from gnomAD v4.1; Associated with Abnormal heart morphology.

What condition is associated with MAPK1 p.Pro323Arg (c.968C>G)?

MAPK1 p.Pro323Arg (c.968C>G) is associated with Abnormal heart morphology, intellectual disability, specific learning disability (ClinVar).

How common is MAPK1 p.Pro323Arg (c.968C>G) in the general population?

MAPK1 p.Pro323Arg (c.968C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPK1 p.Pro323Arg (c.968C>G)?

AlphaMissense predicts likely pathogenic (score 0.9504) — an in-silico prediction, not a clinical call.

MAPK1 p.Pro323Arg

c.968C>G · rs2068678455 · VCV917749

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9504 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Abnormal heart morphology

Computational evidence

Protein change
AlphaMissense	0.9504	likely pathogenic ✓ concordant with ClinVar
REVEL	0.728	pathogenic-leaning
SaProt	LLR -15.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 19 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPK1
Protein: p.Pro323Arg
Coding: c.968C>G
MANE Select: NM_002745
dbSNP: rs2068678455
Type: single nucleotide variant
Location: chr22:21769319 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.99 · 157 PDB
Residue 323: a UniProt-annotated variant site (in ns13; results in increased mapk signaling; increased translocation to the nucleus; reduced interaction with dusp6; no effect on interaction with map2k1); an α-helix

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

Disease context

Abnormal heart morphology — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability specific learning disability

Similar variants

MAPK1 p.Pro323His Likely pathogenic ★ same residue
MAPK1 p.Ala174Val Pathogenic ★★ ⚠ same condition
MAPK1 p.Asp318Asn Pathogenic/Likely pathogenic ★★ same condition
MAPK1 p.Asp318Gly Pathogenic ★★ same condition
MAPK1 p.Glu322Gln Pathogenic/Likely pathogenic ★★ same condition
MAPK1 p.His80Tyr Pathogenic ★★ same condition
MAPK1 p.Ile74Asn Pathogenic ★ same condition
MAPK1 p.Arg135Thr Likely pathogenic ★★ 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-pro323arg (accessed [today's date]).

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