Is AP2A2 p.Ala538= (c.1614G>A) pathogenic?

AP2A2 p.Ala538= (c.1614G>A) is classified Likely benign in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). Rare (popmax 0.281%, mid).

How common is AP2A2 p.Ala538= (c.1614G>A) in the general population?

AP2A2 p.Ala538= (c.1614G>A) is rare (popmax 0.281%, mid) (gnomAD).

AP2A2 p.Ala538=

c.1614G>A · rs201859072 · VCV2641100

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.281%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.8	GERP -3.7
Overall
CADD	4.613	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.281% Middle Eastern · 17/6,058 alleles

Filtering AF 0.233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.222%

Overall 0.256% 4,122/1,608,076 alleles · rare exomes 3,748/1,455,802 · genomes 374/152,274 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.28%	78
Amishnot grpmax-eligible	0.548%	182
Ashkenazi Jewishnot grpmax-eligible	0.375%	266
Middle Easterngrpmax	0.281%	356
South Asian	0.26%	385
Remaining individualsnot grpmax-eligible	0.245%	408
European (non-Finnish)	0.233%	430
Admixed American	0.114%	881
African / African-American	0.0387%	2,587
East Asian	0.00892%	11,207

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala538=
Coding: c.1614G>A
MANE Select: NM_012305
dbSNP: rs201859072
Type: single nucleotide variant
Location: chr11:993817 (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.Ala538Val Uncertain significance ★ ⚠ same residue
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

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-ala538 (accessed [today's date]).

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