Is MAPK1 p.Ala174Val (c.521C>T) pathogenic?

MAPK1 p.Ala174Val (c.521C>T) is classified Pathogenic in MAPK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-12-30). AlphaMissense: likely pathogenic (0.6011); Absent from gnomAD v4.1; Associated with Macrocephaly.

What condition is associated with MAPK1 p.Ala174Val (c.521C>T)?

MAPK1 p.Ala174Val (c.521C>T) is associated with Macrocephaly, specific learning disability, Noonan syndrome 13 (ClinVar).

How common is MAPK1 p.Ala174Val (c.521C>T) in the general population?

MAPK1 p.Ala174Val (c.521C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPK1 p.Ala174Val (c.521C>T)?

AlphaMissense predicts likely pathogenic (score 0.6011) — an in-silico prediction, not a clinical call.

MAPK1 p.Ala174Val

c.521C>T · rs2069052012 · VCV917744

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6011 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Macrocephaly

Computational evidence

Protein change
AlphaMissense	0.6011	likely pathogenic ✓ concordant with ClinVar
REVEL	0.456	indeterminate
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 2.1e-19 · regional, not allelic
Overall
CADD	29.3	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.Ala174Val
Coding: c.521C>T
MANE Select: NM_002745
dbSNP: rs2069052012
Type: single nucleotide variant
Location: chr22:21799100 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.99 · 157 PDB
Residue 174: the protein kinase domain; 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)

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

Disease context

Macrocephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: specific learning disability Noonan syndrome 13

Similar variants

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.Pro323Arg 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-ala174val (accessed [today's date]).

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