Is AP1M2 p.Ala405Thr (c.1213G>A) pathogenic?

AP1M2 p.Ala405Thr (c.1213G>A) is classified Uncertain significance in AP1M2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: likely pathogenic (0.9002); Ultra-rare (popmax 0.0108%, nfe).

How common is AP1M2 p.Ala405Thr (c.1213G>A) in the general population?

AP1M2 p.Ala405Thr (c.1213G>A) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about AP1M2 p.Ala405Thr (c.1213G>A)?

AlphaMissense predicts likely pathogenic (score 0.9002) — an in-silico prediction, not a clinical call.

AP1M2 p.Ala405Thr

c.1213G>A · rs200362172 · VCV2406249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9002 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9002	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -11.35	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.022 · regional, not allelic
Overall
CADD	28.6	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 0.0108% European (non-Finnish) · 125/1,154,360 alleles

Filtering AF 0.00926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00863%

Overall 0.00819% 128/1,563,714 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,235
Remaining individualsnot grpmax-eligible	0.00329%	30,352
Finnishnot grpmax-eligible	0.00164%	60,874

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: AP1M2
Protein: p.Ala405Thr
Coding: c.1213G>A
MANE Select: NM_005498
dbSNP: rs200362172
Type: single nucleotide variant
Location: chr19:10574453 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.03
Residue 405: the mhd domain

Full AP1M2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1M2 p.Ala156Gly Uncertain significance ★ ⚠ same type
AP1M2 p.Ala156Thr Uncertain significance ★ ⚠ same type
AP1M2 p.Ala3Val Uncertain significance ★ ⚠ same type
AP1M2 p.Arg104Gln Uncertain significance ★ ⚠ same type
AP1M2 p.Arg148Gln Uncertain significance ★ ⚠ same type
AP1M2 p.Arg148Trp Uncertain significance ★ ⚠ same type
AP1M2 p.Arg19Cys Uncertain significance ★ ⚠ same type
AP1M2 p.Arg211Trp 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/ap1m2-p-ala405thr (accessed [today's date]).

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