Is AP2A2 p.Ala799Val (c.2396C>T) pathogenic?

AP2A2 p.Ala799Val (c.2396C>T) is classified Uncertain significance in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1273); Ultra-rare (popmax 0.0201%, afr).

How common is AP2A2 p.Ala799Val (c.2396C>T) in the general population?

AP2A2 p.Ala799Val (c.2396C>T) is ultra-rare (popmax 0.0201%, afr) (gnomAD).

What do computational predictors say about AP2A2 p.Ala799Val (c.2396C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

AP2A2 p.Ala799Val

c.2396C>T · VCV4641451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.41	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 10 kb · p 5.7e-07 · regional, not allelic
Overall
CADD	24.4	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 0.0201% African / African-American · 15/74,796 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0099%

Overall 0.0038% 61/1,606,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0201%	4,986
European (non-Finnish)	0.00374%	26,758
Admixed American	0.00168%	59,358
Remaining individualsnot grpmax-eligible	0.00161%	62,190

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: AP2A2
Protein: p.Ala799Val
Coding: c.2396C>T
MANE Select: NM_012305
Type: single nucleotide variant
Location: chr11:1008111 (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-ala799val (accessed [today's date]).

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