Is AP2A1 p.Pro490Ser (c.1468C>T) pathogenic?

AP2A1 p.Pro490Ser (c.1468C>T) is classified Uncertain significance in AP2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: ambiguous (0.5118); Very rare (popmax 0.00113%, sas).

How common is AP2A1 p.Pro490Ser (c.1468C>T) in the general population?

AP2A1 p.Pro490Ser (c.1468C>T) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about AP2A1 p.Pro490Ser (c.1468C>T)?

AlphaMissense predicts ambiguous (score 0.5118) — an in-silico prediction, not a clinical call.

AP2A1 p.Pro490Ser

c.1468C>T · rs2514383434 · VCV2604993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5118	ambiguous
REVEL	0.251	benign-leaning
SaProt	LLR -8.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,894 bp · p 7.1e-28 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00113% South Asian · 1/88,636 alleles

Overall 0.000138% 2/1,449,142 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,636
European (non-Finnish)	8.52e-05%	1,174,260

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: AP2A1
Protein: p.Pro490Ser
Coding: c.1468C>T
MANE Select: NM_130787
dbSNP: rs2514383434
Type: single nucleotide variant
Location: chr19:49800973 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.78

Full AP2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2A1 c.2115-388C>T Benign ★★ same type
AP2A1 p.Ala365= Benign ★★ same type
AP2A1 c.2114+403C>T Uncertain significance ★ ⚠ same type
AP2A1 c.2115-363G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-371C>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-372G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>C Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>G 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/ap2a1-p-pro490ser (accessed [today's date]).

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