Is MAP2K2 p.Leu102Pro (c.305T>C) pathogenic?

MAP2K2 p.Leu102Pro (c.305T>C) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Leu102Pro (c.305T>C)?

MAP2K2 p.Leu102Pro (c.305T>C) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Leu102Pro (c.305T>C) in the general population?

MAP2K2 p.Leu102Pro (c.305T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Leu102Pro (c.305T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

MAP2K2 p.Leu102Pro

c.305T>C · rs1304984012 · VCV2913560

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 8% in MAP2K2
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -14.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,934 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,930 alleles · very rare exomes 2/1,459,682 · genomes 1/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,934
European (non-Finnish)	0.00017%	589,661

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: MAP2K2
Protein: p.Leu102Pro
Coding: c.305T>C
MANE Select: NM_030662
dbSNP: rs1304984012
Type: single nucleotide variant
Location: chr19:4110654 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 102: the protein kinase domain; a β-strand

Full MAP2K2 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

MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His Pathogenic ★★★ same condition
MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ same condition
MAP2K2 p.Arg231Leu Uncertain significance ★★★ ⚠ same condition
MAP2K2 p.Arg281Gln Uncertain significance ★★★ ⚠ 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/map2k2-p-leu102pro (accessed [today's date]).

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