Is MAP3K5 p.Ala422Pro (c.1264G>C) pathogenic?

MAP3K5 p.Ala422Pro (c.1264G>C) is classified Uncertain significance in MAP3K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely pathogenic (0.9908); Very rare (popmax 6.28e-05%).

How common is MAP3K5 p.Ala422Pro (c.1264G>C) in the general population?

MAP3K5 p.Ala422Pro (c.1264G>C) is very rare (popmax 6.28e-05%) (gnomAD).

What do computational predictors say about MAP3K5 p.Ala422Pro (c.1264G>C)?

AlphaMissense predicts likely pathogenic (score 0.9908) — an in-silico prediction, not a clinical call.

MAP3K5 p.Ala422Pro

c.1264G>C · VCV4051345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.28e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9908	likely pathogenic
REVEL	0.271	benign-leaning
SaProt	LLR -16.35	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 169 kb · p 9.4e-10 · regional, not allelic
Overall
CADD	28.9	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 6.28e-05%

Overall 6.28e-05% 1/1,593,142 alleles · very rare exomes 1/1,440,906 · genomes 0/152,236 · 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: MAP3K5
Protein: p.Ala422Pro
Coding: c.1264G>C
MANE Select: NM_005923
Type: single nucleotide variant
Location: chr6:136669385 (GRCh38)
Gene constraint: LOEUF 0.433 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.87 · 27 PDB
Residue 422: an α-helix

Full MAP3K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K5 p.Ala1162Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala1166Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala1322Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala283Val Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala909Thr Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1014Gln Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1239Trp Uncertain significance ★ ⚠ same type
MAP3K5 p.Arg1272Gly 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/map3k5-p-ala422pro (accessed [today's date]).

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