Is MAP2K1 p.Thr23= (c.69C>T) pathogenic?

MAP2K1 p.Thr23= (c.69C>T) is classified Likely benign in MAP2K1 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). Rare (popmax 0.16%, afr); Associated with RASopathy.

What condition is associated with MAP2K1 p.Thr23= (c.69C>T)?

MAP2K1 p.Thr23= (c.69C>T) is associated with RASopathy (ClinVar).

How common is MAP2K1 p.Thr23= (c.69C>T) in the general population?

MAP2K1 p.Thr23= (c.69C>T) is rare (popmax 0.16%, afr) (gnomAD).

MAP2K1 p.Thr23=

c.69C>T · rs140749690 · VCV138155

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.16%, afr)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Likely Benign for RASopathy. Applied ACMG criteria (verbatim):

BS1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.69C>T (p.Thr23=) variant in the MAP2K1 gene is 0.0484% (4/2820) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; 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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP 0.4, phastCons 1
Overall
CADD	14.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.16% African / African-American · 118/73,776 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.00911% 142/1,559,168 alleles · rare exomes 64/1,406,886 · genomes 78/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.16%	625
Remaining individualsnot grpmax-eligible	0.0248%	4,024
Admixed American	0.00578%	17,293
European (non-Finnish)	0.000521%	191,804

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.Thr23=
Coding: c.69C>T
MANE Select: NM_002755
dbSNP: rs140749690
Type: single nucleotide variant
Location: chr15:66387416 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 23: the 'disordered' region

Full MAP2K1 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

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
MAP2K1 p.Lys57Gln 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/map2k1-p-thr23 (accessed [today's date]).

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