Is AP2A2 p.Ala304Val (c.911C>T) pathogenic?

AP2A2 p.Ala304Val (c.911C>T) is classified Uncertain significance in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.9106); Ultra-rare (popmax 0.0426%, afr).

How common is AP2A2 p.Ala304Val (c.911C>T) in the general population?

AP2A2 p.Ala304Val (c.911C>T) is ultra-rare (popmax 0.0426%, afr) (gnomAD).

What do computational predictors say about AP2A2 p.Ala304Val (c.911C>T)?

AlphaMissense predicts likely pathogenic (score 0.9106) — an in-silico prediction, not a clinical call.

AP2A2 p.Ala304Val

c.911C>T · VCV3403627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9106	likely pathogenic
REVEL	0.345	indeterminate
SaProt	LLR -12.54	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 22 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	25.4	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 0.0426% African / African-American · 32/75,030 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00248% 40/1,613,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0426%	2,345
South Asian	0.00329%	30,361
European (non-Finnish)	0.000424%	235,980

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.Ala304Val
Coding: c.911C>T
MANE Select: NM_012305
Type: single nucleotide variant
Location: chr11:985531 (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.Ala375Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala3Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala435Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala488Thr 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-ala304val (accessed [today's date]).

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