Is MAP3K13 p.Arg449Gln (c.1346G>A) pathogenic?

MAP3K13 p.Arg449Gln (c.1346G>A) is classified Uncertain significance in MAP3K13 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: ambiguous (0.4375); Ultra-rare (popmax 0.0167%, amr).

How common is MAP3K13 p.Arg449Gln (c.1346G>A) in the general population?

MAP3K13 p.Arg449Gln (c.1346G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about MAP3K13 p.Arg449Gln (c.1346G>A)?

AlphaMissense predicts ambiguous (score 0.4375) — an in-silico prediction, not a clinical call.

MAP3K13 p.Arg449Gln

c.1346G>A · rs201739097 · VCV2592256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4375	ambiguous
REVEL	0.363	indeterminate
SaProt	LLR -8.17	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 32 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	29.0	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 0.0167% Admixed American · 10/59,994 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00143% 23/1,613,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0048%	20,822
South Asian	0.0022%	45,476
African / African-American	0.00133%	75,032
European (non-Finnish)	0.000594%	168,474

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: MAP3K13
Protein: p.Arg449Gln
Coding: c.1346G>A
MANE Select: NM_004721
dbSNP: rs201739097
Type: single nucleotide variant
Location: chr3:185463617 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.92
Residue 449: the 'leucine-zipper 1' region

Full MAP3K13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K13 p.Ala416Thr Uncertain significance ★ ⚠ same type
MAP3K13 p.Ala465Thr Uncertain significance ★ ⚠ same type
MAP3K13 p.Ala96Val Uncertain significance ★ ⚠ same type
MAP3K13 p.Arg278His Uncertain significance ★ ⚠ same type
MAP3K13 p.Arg326Trp Uncertain significance ★ ⚠ same type
MAP3K13 p.Arg401Gln Uncertain significance ★ ⚠ same type
MAP3K13 p.Arg474Gln Uncertain significance ★ ⚠ same type
MAP3K13 p.Arg478Gln 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/map3k13-p-arg449gln (accessed [today's date]).

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