Is AP2M1 p.Val296Ala (c.887T>C) pathogenic?

AP2M1 p.Val296Ala (c.887T>C) is classified Uncertain significance in AP2M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). AlphaMissense: likely benign (0.2033); Very rare (popmax 8.47e-05%, nfe).

How common is AP2M1 p.Val296Ala (c.887T>C) in the general population?

AP2M1 p.Val296Ala (c.887T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AP2M1 p.Val296Ala (c.887T>C)?

AlphaMissense predicts likely benign (score 0.2033) — an in-silico prediction, not a clinical call.

AP2M1 p.Val296Ala

c.887T>C · rs1715288049 · VCV1719924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2033 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2033	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,621 bp · p 8.1e-19 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 0.000657% 1/152,122 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.Val296Ala
Coding: c.887T>C
MANE Select: NM_004068
dbSNP: rs1715288049
Type: single nucleotide variant
Location: chr3:184181971 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 296: 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-val296ala (accessed [today's date]).

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