Is MAP3K12 p.Lys577Arg (c.1730A>G) pathogenic?

MAP3K12 p.Lys577Arg (c.1730A>G) is classified Uncertain significance in MAP3K12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.1129); Rare (popmax 0.191%, amr).

How common is MAP3K12 p.Lys577Arg (c.1730A>G) in the general population?

MAP3K12 p.Lys577Arg (c.1730A>G) is rare (popmax 0.191%, amr) (gnomAD).

What do computational predictors say about MAP3K12 p.Lys577Arg (c.1730A>G)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

MAP3K12 p.Lys577Arg

c.1730A>G · rs755903927 · VCV2385921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.191%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,240 bp · p 0.77 · regional, not allelic
Overall
CADD	25.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K544R vs ClinVar K577R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.191% Admixed American · 90/47,220 alleles

Filtering AF 0.159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.00604% 93/1,538,542 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.191%	525
Remaining individualsnot grpmax-eligible	0.00508%	19,683

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: MAP3K12
Protein: p.Lys577Arg
Coding: c.1730A>G
MANE Select: NM_001193511
dbSNP: rs755903927
Type: single nucleotide variant
Location: chr12:53483073 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.80 · 12 PDB
Residue 577: the 'disordered' region

Full MAP3K12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K12 p.Gly661Arg Uncertain significance ★★ ⚠ same type
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MAP3K12 p.Ala671Asp Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg106Gln Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg176Cys Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg236Trp Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg488Lys Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg572Gln 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/map3k12-p-lys577arg (accessed [today's date]).

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