Is MAP2K2 p.Thr386Ile (c.1157C>T) pathogenic?

MAP2K2 p.Thr386Ile (c.1157C>T) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-06). AlphaMissense: likely benign (0.182); Very rare (popmax 0.00136%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Thr386Ile (c.1157C>T)?

MAP2K2 p.Thr386Ile (c.1157C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Thr386Ile (c.1157C>T) in the general population?

MAP2K2 p.Thr386Ile (c.1157C>T) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Thr386Ile (c.1157C>T)?

AlphaMissense predicts likely benign (score 0.182) — an in-silico prediction, not a clinical call.

MAP2K2 p.Thr386Ile

c.1157C>T · rs2145036510 · VCV1506401

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.182	likely benign
REVEL	0.499	indeterminate
SaProt	LLR -7.78	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 11	GERP 0.74, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	24.7	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 0.00136% African / African-American · 1/73,522 alleles

Overall 0.000128% 2/1,557,310 alleles · very rare exomes 2/1,404,980 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,522
South Asian	0.00118%	84,578

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.Thr386Ile
Coding: c.1157C>T
MANE Select: NM_030662
dbSNP: rs2145036510
Type: single nucleotide variant
Location: chr19:4090644 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 386: an α-helix

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

Similar variants

MAP2K2 p.Thr386Asn Uncertain significance ★ same residue
MAP2K2 p.Thr386= Likely benign ★ same residue
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

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-thr386ile (accessed [today's date]).

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