Is MAPK3 p.Leu167Val (c.499C>G) pathogenic?

MAPK3 p.Leu167Val (c.499C>G) is classified Uncertain significance in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.853); Very rare (popmax 0.00333%, amr).

How common is MAPK3 p.Leu167Val (c.499C>G) in the general population?

MAPK3 p.Leu167Val (c.499C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MAPK3 p.Leu167Val (c.499C>G)?

AlphaMissense predicts likely pathogenic (score 0.853) — an in-silico prediction, not a clinical call.

MAPK3 p.Leu167Val

c.499C>G · VCV4051580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.853	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -13.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.4, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 4,193 bp · p 4.2e-06 · regional, not allelic
Overall
CADD	23.0	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 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,768 alleles · very rare exomes 2/1,461,616 · genomes 3/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.00017%	589,929

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: MAPK3
Protein: p.Leu167Val
Coding: c.499C>G
MANE Select: NM_002746
Type: single nucleotide variant
Location: chr16:30118393 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.09 · 8 PDB
Residue 167: the protein kinase domain

Full MAPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK3 p.Gly11= Likely benign ★★ same type
MAPK3 p.Pro336= Benign/Likely benign ★★ same type
MAPK3 p.Tyr148Cys Likely pathogenic ★ same type
MAPK3 p.Ala378Asp Uncertain significance ★ ⚠ same type
MAPK3 p.Arg15Ser Uncertain significance ★ ⚠ same type
MAPK3 p.Arg242Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gly 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/mapk3-p-leu167val (accessed [today's date]).

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