Is AP2A1 p.Asn325Ser (c.974A>G) pathogenic?

AP2A1 p.Asn325Ser (c.974A>G) is classified Uncertain significance in AP2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely benign (0.0666); Ultra-rare (popmax 0.0329%, mid).

How common is AP2A1 p.Asn325Ser (c.974A>G) in the general population?

AP2A1 p.Asn325Ser (c.974A>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about AP2A1 p.Asn325Ser (c.974A>G)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

AP2A1 p.Asn325Ser

c.974A>G · VCV3876706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.23	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 6.2	GERP 0.27, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,894 bp · p 7.1e-28 · regional, not allelic
Overall
CADD	23.0	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00168% 27/1,610,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
South Asian	0.0022%	45,428
European (non-Finnish)	0.0017%	58,969
Admixed American	0.00167%	59,880
Remaining individualsnot grpmax-eligible	0.0016%	62,386
African / African-American	0.00134%	74,798

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.Asn325Ser
Coding: c.974A>G
MANE Select: NM_130787
Type: single nucleotide variant
Location: chr19:49799335 (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-asn325ser (accessed [today's date]).

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