Is AP2A2 p.Leu920Val (c.2758C>G) pathogenic?

AP2A2 p.Leu920Val (c.2758C>G) is classified Uncertain significance in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: likely benign (0.0825); Absent from gnomAD v4.1.

How common is AP2A2 p.Leu920Val (c.2758C>G) in the general population?

AP2A2 p.Leu920Val (c.2758C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP2A2 p.Leu920Val (c.2758C>G)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

AP2A2 p.Leu920Val

c.2758C>G · VCV3403718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -9.18	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 2.3	GERP -1.7, phastCons 0.99
Regional constraint	o/e 0.72	unconstrained · MANE · 10 kb · p 5.7e-07 · regional, not allelic
Overall
CADD	19.55	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

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: AP2A2
Protein: p.Leu920Val
Coding: c.2758C>G
MANE Select: NM_012305
Type: single nucleotide variant
Location: chr11:1010563 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.30

Full AP2A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2A2 p.Ala136Ser Uncertain significance ★ ⚠ same type
AP2A2 p.Ala136Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala168Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala274Pro Uncertain significance ★ ⚠ same type
AP2A2 p.Ala304Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala375Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala3Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala435Val 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/ap2a2-p-leu920val (accessed [today's date]).

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