Is MAP2K4 p.Ala378Pro (c.1132G>C) pathogenic?

MAP2K4 p.Ala378Pro (c.1132G>C) is classified Uncertain significance in MAP2K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: ambiguous (0.3716); Absent from gnomAD v4.1.

How common is MAP2K4 p.Ala378Pro (c.1132G>C) in the general population?

MAP2K4 p.Ala378Pro (c.1132G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K4 p.Ala378Pro (c.1132G>C)?

AlphaMissense predicts ambiguous (score 0.3716) — an in-silico prediction, not a clinical call.

MAP2K4 p.Ala378Pro

c.1132G>C · VCV3870101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3716 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.3716	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -8.47	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 12 kb · p 0.003 · regional, not allelic
Overall
CADD	26.5	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: MAP2K4
Protein: p.Ala378Pro
Coding: c.1132G>C
MANE Select: NM_003010
Type: single nucleotide variant
Location: chr17:12141192 (GRCh38)
Gene constraint: LOEUF 0.216 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 4 PDB
Residue 378: the 'dvd domain' region; an α-helix

Full MAP2K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K4 c.116-2A>C Uncertain significance ★ same type
MAP2K4 p.Ala33Val Uncertain significance ★ ⚠ same type
MAP2K4 p.Arg262Gly Uncertain significance ★ ⚠ same type
MAP2K4 p.Arg58Gly Uncertain significance ★ same type
MAP2K4 p.Asn242Ser Uncertain significance ★ ⚠ same type
MAP2K4 p.Asp157Glu Uncertain significance ★ ⚠ same type
MAP2K4 p.Gln316Leu Uncertain significance ★ ⚠ same type
MAP2K4 p.Gly11Arg 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/map2k4-p-ala378pro (accessed [today's date]).

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