Is MAP2K5 p.Val233Ala (c.698T>C) pathogenic?

MAP2K5 p.Val233Ala (c.698T>C) is classified Uncertain significance in MAP2K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.2053); Very rare (popmax 0.00896%, eas).

How common is MAP2K5 p.Val233Ala (c.698T>C) in the general population?

MAP2K5 p.Val233Ala (c.698T>C) is very rare (popmax 0.00896%, eas) (gnomAD).

What do computational predictors say about MAP2K5 p.Val233Ala (c.698T>C)?

AlphaMissense predicts likely benign (score 0.2053) — an in-silico prediction, not a clinical call.

MAP2K5 p.Val233Ala

c.698T>C · rs763833942 · VCV3122787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00896%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2053	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 160 kb · p 4.7e-09 · 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 0.00896% East Asian · 4/44,628 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.00025% 4/1,602,030 alleles · very rare exomes 3/1,449,876 · genomes 1/152,154 · 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: MAP2K5
Protein: p.Val233Ala
Coding: c.698T>C
MANE Select: NM_145160
dbSNP: rs763833942
Type: single nucleotide variant
Location: chr15:67646431 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.20 · 3 PDB
Residue 233: the protein kinase domain

Full MAP2K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K5 c.586-8A>G Benign ★★ same type
MAP2K5 c.1074+1G>A Uncertain significance ★ same type
MAP2K5 p.Ala150Ser Uncertain significance ★ ⚠ same type
MAP2K5 p.Ala157Thr Uncertain significance ★ ⚠ same type
MAP2K5 p.Ala266Val Uncertain significance ★ ⚠ same type
MAP2K5 p.Ala437Ser Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Gln Uncertain significance ★ ⚠ same type
MAP2K5 p.Arg125Trp Uncertain significance ★ same type

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/map2k5-p-val233ala (accessed [today's date]).

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