Is AP2M1 p.Arg423His (c.1268G>A) pathogenic?

AP2M1 p.Arg423His (c.1268G>A) is classified Uncertain significance in AP2M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely pathogenic (0.9977); Absent from gnomAD v4.1.

How common is AP2M1 p.Arg423His (c.1268G>A) in the general population?

AP2M1 p.Arg423His (c.1268G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP2M1 p.Arg423His (c.1268G>A)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

AP2M1 p.Arg423His

c.1268G>A · VCV4526341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -12.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.64, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 43 bp · p 4.4e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: AP2M1
Protein: p.Arg423His
Coding: c.1268G>A
MANE Select: NM_004068
Type: single nucleotide variant
Location: chr3:184183576 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 423: the mhd domain; a β-strand

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

Similar variants

AP2M1 p.Arg170Trp Pathogenic/Likely pathogenic ★★ same type
AP2M1 p.Ala28Thr Uncertain significance ★★ ⚠ same type
AP2M1 p.Arg169His Uncertain significance ★★ ⚠ same type
AP2M1 p.Arg199Gln Uncertain significance ★★ ⚠ same type
AP2M1 p.Arg40Trp Uncertain significance ★★ ⚠ same type
AP2M1 p.Arg44His Uncertain significance ★★ ⚠ same type
AP2M1 p.Cys246Arg Uncertain significance ★★ ⚠ same type
AP2M1 p.Cys86Tyr 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/ap2m1-p-arg423his (accessed [today's date]).

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