Is MAPK1 p.Ile255Val (c.763A>G) pathogenic?

MAPK1 p.Ile255Val (c.763A>G) is classified Conflicting classifications of pathogenicity in MAPK1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-24). AlphaMissense: likely benign (0.3216); Very rare (popmax 0.00536%, afr); Associated with Noonan syndrome 13.

What condition is associated with MAPK1 p.Ile255Val (c.763A>G)?

MAPK1 p.Ile255Val (c.763A>G) is associated with Noonan syndrome 13 (ClinVar).

How common is MAPK1 p.Ile255Val (c.763A>G) in the general population?

MAPK1 p.Ile255Val (c.763A>G) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about MAPK1 p.Ile255Val (c.763A>G)?

AlphaMissense predicts likely benign (score 0.3216) — an in-silico prediction, not a clinical call.

MAPK1 p.Ile255Val

c.763A>G · rs375334289 · VCV1299571

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome 13

Computational evidence

Protein change
AlphaMissense	0.3216	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.71	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 19 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	24.7	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 0.00536% African / African-American · 4/74,678 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000435% 7/1,610,122 alleles · very rare exomes 4/1,457,892 · genomes 3/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,669
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,546
European (non-Finnish)	0.00017%	589,227

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.Ile255Val
Coding: c.763A>G
MANE Select: NM_002745
dbSNP: rs375334289
Type: single nucleotide variant
Location: chr22:21788350 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.99 · 157 PDB
Residue 255: the protein kinase domain

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

Disease context

Noonan syndrome 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.Asn82Asp Likely pathogenic ★ same condition
MAPK1 p.Ile74Asn Pathogenic ★ same condition
MAPK1 p.Tyr316His Likely pathogenic ★ same condition

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-ile255val (accessed [today's date]).

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