Is AP2A2 p.Thr248Ala (c.742A>G) pathogenic?

AP2A2 p.Thr248Ala (c.742A>G) is classified Uncertain significance in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.5913); Very rare (popmax 0.00102%, nfe).

How common is AP2A2 p.Thr248Ala (c.742A>G) in the general population?

AP2A2 p.Thr248Ala (c.742A>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about AP2A2 p.Thr248Ala (c.742A>G)?

AlphaMissense predicts likely pathogenic (score 0.5913) — an in-silico prediction, not a clinical call.

AP2A2 p.Thr248Ala

c.742A>G · VCV4114872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5913	likely pathogenic
REVEL	0.268	benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 22 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	28.3	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 0.00102% European (non-Finnish) · 12/1,179,700 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,390 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: AP2A2
Protein: p.Thr248Ala
Coding: c.742A>G
MANE Select: NM_012305
Type: single nucleotide variant
Location: chr11:984681 (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-thr248ala (accessed [today's date]).

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