Is APBA3 p.Glu552Lys (c.1654G>A) pathogenic?

APBA3 p.Glu552Lys (c.1654G>A) is classified Uncertain significance in APBA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1841); Ultra-rare (popmax 0.0199%, nfe).

How common is APBA3 p.Glu552Lys (c.1654G>A) in the general population?

APBA3 p.Glu552Lys (c.1654G>A) is ultra-rare (popmax 0.0199%, nfe) (gnomAD).

What do computational predictors say about APBA3 p.Glu552Lys (c.1654G>A)?

AlphaMissense predicts likely benign (score 0.1841) — an in-silico prediction, not a clinical call.

APBA3 p.Glu552Lys

c.1654G>A · rs368800499 · VCV2511793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1841	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -11.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.64, phastCons 0.44
Regional constraint	o/e 1.05	unconstrained · MANE · 9,235 bp · p 0.12 · regional, not allelic
Overall
CADD	25.3	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 0.0199% European (non-Finnish) · 228/1,148,312 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.0168% 260/1,551,834 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0349%	2,863
European (non-Finnish)grpmax	0.0199%	5,036
Admixed American	0.00586%	17,066
African / African-American	0.00546%	18,329
East Asian	0.00242%	41,290
South Asian	0.00237%	42,125
Finnishnot grpmax-eligible	0.00171%	58,420

Remaining individuals 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: APBA3
Protein: p.Glu552Lys
Coding: c.1654G>A
MANE Select: NM_004886
dbSNP: rs368800499
Type: single nucleotide variant
Location: chr19:3751191 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.79 · 3 PDB
Residue 552: the pdz 2 domain; a β-strand

Full APBA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBA3 p.Ala158Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala202Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala223Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala308Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala317Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala335Thr Uncertain significance ★ ⚠ same type
APBA3 p.Ala335Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala351Thr 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/apba3-p-glu552lys (accessed [today's date]).

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