Is AP1M2 p.Asn180Lys (c.540C>A) pathogenic?

AP1M2 p.Asn180Lys (c.540C>A) is classified Uncertain significance in AP1M2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.9756); Very rare (popmax 8.48e-05%, nfe).

How common is AP1M2 p.Asn180Lys (c.540C>A) in the general population?

AP1M2 p.Asn180Lys (c.540C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about AP1M2 p.Asn180Lys (c.540C>A)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

AP1M2 p.Asn180Lys

c.540C>A · VCV4114638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic
REVEL	0.311	indeterminate
SaProt	LLR -13.68	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 2.5	GERP -0.56, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.022 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,830 alleles

Overall 6.84e-05% 1/1,461,620 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: AP1M2
Protein: p.Asn180Lys
Coding: c.540C>A
MANE Select: NM_005498
Type: single nucleotide variant
Location: chr19:10581493 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.03
Residue 180: 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.Ala405Thr 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

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-asn180lys (accessed [today's date]).

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