Is MAP2K2 p.Val64= (c.192C>T) pathogenic?

MAP2K2 p.Val64= (c.192C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). Common (popmax 7.76%, sas) — too common for a highly-penetrant pathogenic allele; Associated with RASopathy.

What condition is associated with MAP2K2 p.Val64= (c.192C>T)?

MAP2K2 p.Val64= (c.192C>T) is associated with RASopathy, cardiofaciocutaneous syndrome 4 (ClinVar).

MAP2K2 p.Val64=

Q: How common is MAP2K2 p.Val64= (c.192C>T) in the general population?

MAP2K2 p.Val64= (c.192C>T) is common (popmax 7.76%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.192C>T · rs8157 · VCV40770

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 7.76%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.1	GERP -3.9
Overall
CADD	6.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.76% South Asian · 7,070/91,090 alleles

Filtering AF 7.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.55%

Overall 6.25% 100,893/1,614,010 alleles · common exomes 91,175/1,461,766 · genomes 9,718/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	7.76%	13
Finnishnot grpmax-eligible	7.72%	13
African / African-American	7.64%	13
European (non-Finnish)	6.35%	16
Remaining individualsnot grpmax-eligible	5.94%	17
Middle Eastern	5.49%	18
Ashkenazi Jewishnot grpmax-eligible	5.32%	19
Admixed American	3.3%	30
East Asian	1.48%	68
Amishnot grpmax-eligible	1.43%	70

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.Val64=
Coding: c.192C>T
MANE Select: NM_030662
dbSNP: rs8157
Type: single nucleotide variant
Location: chr19:4117530 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: cardiofaciocutaneous syndrome 4

Similar variants

MAP2K2 p.Val64Phe Likely pathogenic ★★ same residue
MAP2K2 p.Val64Gly Likely pathogenic same residue
MAP2K2 p.Val64Ala Uncertain significance ★ ⚠ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys 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/map2k2-p-val64 (accessed [today's date]).

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