Is MAP3K8 p.Pro349Arg (c.1046C>G) pathogenic?

MAP3K8 p.Pro349Arg (c.1046C>G) is classified Uncertain significance in MAP3K8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.987); Absent from gnomAD v4.1.

How common is MAP3K8 p.Pro349Arg (c.1046C>G) in the general population?

MAP3K8 p.Pro349Arg (c.1046C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K8 p.Pro349Arg (c.1046C>G)?

AlphaMissense predicts likely pathogenic (score 0.987) — an in-silico prediction, not a clinical call.

MAP3K8 p.Pro349Arg

c.1046C>G · rs1301937436 · VCV2340089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.987	likely pathogenic
REVEL	0.38	indeterminate
SaProt	LLR -6.66	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 5.9	GERP 0.61, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 20 kb · p 1.5e-16 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP3K8
Protein: p.Pro349Arg
Coding: c.1046C>G
MANE Select: NM_005204
dbSNP: rs1301937436
Type: single nucleotide variant
Location: chr10:30459274 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI 0.73 (gnomAD)
Structure: AlphaFold pLDDT 74.13 · 3 PDB
Residue 349: the protein kinase domain

Full MAP3K8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K8 p.Ala35Ser Uncertain significance ★★ ⚠ same type
MAP3K8 p.Ala450Thr Uncertain significance ★★ same type
MAP3K8 p.Arg392Gly Uncertain significance ★★ ⚠ same type
MAP3K8 p.Arg408Ser Uncertain significance ★★ ⚠ same type
MAP3K8 p.Asn54Asp Uncertain significance ★★ ⚠ same type
MAP3K8 p.Gly67Asp Uncertain significance ★★ ⚠ same type
MAP3K8 p.Ile190Val Uncertain significance ★★ ⚠ same type
MAP3K8 p.Met277Ile 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/map3k8-p-pro349arg (accessed [today's date]).

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