Is AP2M1 p.Arg199Trp (c.595C>T) pathogenic?

AP2M1 p.Arg199Trp (c.595C>T) is classified Likely benign in AP2M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely pathogenic (0.7768); Very rare (popmax 6.84e-05%).

How common is AP2M1 p.Arg199Trp (c.595C>T) in the general population?

AP2M1 p.Arg199Trp (c.595C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about AP2M1 p.Arg199Trp (c.595C>T)?

AlphaMissense predicts likely pathogenic (score 0.7768) — an in-silico prediction, not a clinical call.

AP2M1 p.Arg199Trp

c.595C>T · rs2473723976 · VCV2087380

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7768	likely pathogenic
REVEL	0.302	indeterminate
SaProt	LLR -13.54	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 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 4,753 bp · p 1.5e-32 · regional, not allelic
Overall
CADD	34.0	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 6.84e-05%

Overall 6.84e-05% 1/1,461,886 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.Arg199Trp
Coding: c.595C>T
MANE Select: NM_004068
dbSNP: rs2473723976
Type: single nucleotide variant
Location: chr3:184181114 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 199: the mhd domain; a β-strand

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

Similar variants

AP2M1 p.Arg199Gln Uncertain significance ★★ ⚠ same residue
AP2M1 p.Arg170Trp Pathogenic/Likely pathogenic ★★ same type
AP2M1 p.Ala28Thr Uncertain significance ★★ ⚠ same type
AP2M1 p.Arg169His 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-arg199trp (accessed [today's date]).

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