Is MAP3K14 p.Met4Ile (c.12G>A) pathogenic?

MAP3K14 p.Met4Ile (c.12G>A) is classified Uncertain significance in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.8501); Very rare (popmax 0.00017%, nfe).

How common is MAP3K14 p.Met4Ile (c.12G>A) in the general population?

MAP3K14 p.Met4Ile (c.12G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MAP3K14 p.Met4Ile (c.12G>A)?

AlphaMissense predicts likely pathogenic (score 0.8501) — an in-silico prediction, not a clinical call.

MAP3K14 p.Met4Ile

c.12G>A · VCV4549405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8501	likely pathogenic
REVEL	0.184	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 3,895 bp · p 1.6e-12 · regional, not allelic
Overall
CADD	25.6	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 0.00017% European (non-Finnish) · 2/1,179,440 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,078 alleles · very rare exomes 2/1,461,174 · genomes 0/151,904 · joint denominator

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: MAP3K14
Protein: p.Met4Ile
Coding: c.12G>A
MANE Select: NM_003954
Type: single nucleotide variant
Location: chr17:45290734 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB
Residue 4: the 'disordered' region

Full MAP3K14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K14 p.Ala103Thr Uncertain significance ★★ ⚠ same type
MAP3K14 p.Ala142Ser Uncertain significance ★★ ⚠ same type
MAP3K14 p.Ala575Thr Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg131His Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg146Gln Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg218Gln Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg432Trp Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg99His 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/map3k14-p-met4ile (accessed [today's date]).

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