Is MAP2K3 p.Val174Leu (c.520G>C) pathogenic?

MAP2K3 p.Val174Leu (c.520G>C) is classified Uncertain significance in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.6469); Ultra-rare (popmax 0.022%, sas).

How common is MAP2K3 p.Val174Leu (c.520G>C) in the general population?

MAP2K3 p.Val174Leu (c.520G>C) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about MAP2K3 p.Val174Leu (c.520G>C)?

AlphaMissense predicts likely pathogenic (score 0.6469) — an in-silico prediction, not a clinical call.

MAP2K3 p.Val174Leu

c.520G>C · VCV4103136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6469	likely pathogenic
REVEL	0.423	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 20 kb · p 0.26 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.022% South Asian · 20/91,012 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00149% 24/1,614,044 alleles · ultra-rare exomes 23/1,461,738 · genomes 1/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,551
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.000169%	590,033

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: MAP2K3
Protein: p.Val174Leu
Coding: c.520G>C
MANE Select: NM_145109
Type: single nucleotide variant
Location: chr17:21303186 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 174: the protein kinase domain

Full MAP2K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same type
MAP2K3 c.568+10C>T Benign ★★ same type
MAP2K3 p.Ala220= Benign ★★ same type
MAP2K3 p.Ala225= Likely benign ★★ same type
MAP2K3 p.Leu25= Benign ★★ same type
MAP2K3 p.Leu319= Likely benign ★★ same type
MAP2K3 p.Pro40Thr Benign ★★ same type
MAP2K3 p.Ser286= Likely benign ★★ 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/map2k3-p-val174leu (accessed [today's date]).

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