Is MAP2K1 p.Ala32Val (c.95C>T) pathogenic?

MAP2K1 p.Ala32Val (c.95C>T) is classified Uncertain significance in MAP2K1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.2125); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K1 p.Ala32Val (c.95C>T)?

MAP2K1 p.Ala32Val (c.95C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K1 p.Ala32Val (c.95C>T) in the general population?

MAP2K1 p.Ala32Val (c.95C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MAP2K1 p.Ala32Val (c.95C>T)?

AlphaMissense predicts likely benign (score 0.2125) — an in-silico prediction, not a clinical call.

MAP2K1 p.Ala32Val

c.95C>T · rs1203670813 · VCV1767521

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2125	likely benign
REVEL	0.448	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.71, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 94 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,246 alleles · very rare exomes 0/1,461,078 · genomes 2/152,168 · joint denominator

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: MAP2K1
Protein: p.Ala32Val
Coding: c.95C>T
MANE Select: NM_002755
dbSNP: rs1203670813
Type: single nucleotide variant
Location: chr15:66435041 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB

Full MAP2K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: RASopathy

Similar variants

MAP2K1 p.Ala32= Likely benign ★ same residue
MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
MAP2K1 p.Glu203Gly Pathogenic ★★★ same condition
MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same condition
MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Leu92Arg 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/map2k1-p-ala32val (accessed [today's date]).

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