Is APBB3 p.Asp474Glu (c.1422T>A) pathogenic?

APBB3 p.Asp474Glu (c.1422T>A) is classified Uncertain significance in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1129); Ultra-rare (popmax 0.0933%, amr).

How common is APBB3 p.Asp474Glu (c.1422T>A) in the general population?

APBB3 p.Asp474Glu (c.1422T>A) is ultra-rare (popmax 0.0933%, amr) (gnomAD).

What do computational predictors say about APBB3 p.Asp474Glu (c.1422T>A)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

APBB3 p.Asp474Glu

c.1422T>A · VCV4117821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.35	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 3.1	GERP 0.74, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,790 bp · p 0.64 · regional, not allelic
Overall
CADD	14.83	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 0.0933% Admixed American · 56/60,012 alleles

Filtering AF 0.0737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0667%

Overall 0.00558% 90/1,614,204 alleles · ultra-rare exomes 53/1,461,858 · genomes 37/152,346 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0933%	1,072
Remaining individualsnot grpmax-eligible	0.0176%	5,682
African / African-American	0.004%	25,020
European (non-Finnish)	0.00169%	59,002

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: APBB3
Protein: p.Asp474Glu
Coding: c.1422T>A
MANE Select: NM_133173
Type: single nucleotide variant
Location: chr5:140558624 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.76 · 2 PDB

Full APBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB3 p.Ala135Gly Uncertain significance ★ ⚠ same type
APBB3 p.Ala151Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala163Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala288Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala313Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala475Asp Uncertain significance ★ ⚠ same type
APBB3 p.Arg122Cys Uncertain significance ★ ⚠ same type
APBB3 p.Arg154Cys 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/apbb3-p-asp474glu (accessed [today's date]).

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