Is AP2M1 p.Val352Met (c.1054G>A) pathogenic?

AP2M1 p.Val352Met (c.1054G>A) is classified Uncertain significance in AP2M1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-26). AlphaMissense: ambiguous (0.3522); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP2M1 p.Val352Met (c.1054G>A)?

AP2M1 p.Val352Met (c.1054G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP2M1 p.Val352Met (c.1054G>A) in the general population?

AP2M1 p.Val352Met (c.1054G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about AP2M1 p.Val352Met (c.1054G>A)?

AlphaMissense predicts ambiguous (score 0.3522) — an in-silico prediction, not a clinical call.

AP2M1 p.Val352Met

c.1054G>A · rs1006265324 · VCV2654309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3522	ambiguous
REVEL	0.475	indeterminate
SaProt	LLR -8.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,621 bp · p 8.1e-19 · regional, not allelic
Overall
CADD	32.0	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 0.000424% European (non-Finnish) · 5/1,179,986 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,902 alleles · very rare

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: AP2M1
Protein: p.Val352Met
Coding: c.1054G>A
MANE Select: NM_004068
dbSNP: rs1006265324
Type: single nucleotide variant
Location: chr3:184182241 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 352: the mhd domain; a β-strand

Full AP2M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP2M1 p.Ala28Thr Uncertain significance ★★ ⚠ same condition
AP2M1 p.Arg169His Uncertain significance ★★ ⚠ same condition
AP2M1 p.Arg40Trp Uncertain significance ★★ ⚠ same condition
AP2M1 p.Ser97Gly Uncertain significance ★★ ⚠ same condition
AP2M1 p.Ala194Asp Uncertain significance ★ ⚠ same condition
AP2M1 p.Ala67Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
AP2M1 p.Arg162Gln Uncertain significance ★ ⚠ same condition
AP2M1 p.Arg357His Uncertain significance ★ ⚠ same condition

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/ap2m1-p-val352met (accessed [today's date]).

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