Is APBB3 p.Ala475Asp (c.1424C>A) pathogenic?

APBB3 p.Ala475Asp (c.1424C>A) is classified Uncertain significance in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-27). AlphaMissense: ambiguous (0.4368); Ultra-rare (popmax 0.0231%, sas).

How common is APBB3 p.Ala475Asp (c.1424C>A) in the general population?

APBB3 p.Ala475Asp (c.1424C>A) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about APBB3 p.Ala475Asp (c.1424C>A)?

AlphaMissense predicts ambiguous (score 0.4368) — an in-silico prediction, not a clinical call.

APBB3 p.Ala475Asp

c.1424C>A · VCV4860198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4368 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4368	ambiguous
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.8	GERP 0.85, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,790 bp · p 0.64 · regional, not allelic
Overall
CADD	23.6	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 0.0231% South Asian · 21/91,084 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0013% 21/1,614,186 alleles · ultra-rare exomes 20/1,461,854 · genomes 1/152,332 · joint denominator

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.Ala475Asp
Coding: c.1424C>A
MANE Select: NM_133173
Type: single nucleotide variant
Location: chr5:140558622 (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.Arg122Cys Uncertain significance ★ ⚠ same type
APBB3 p.Arg154Cys Uncertain significance ★ ⚠ same type
APBB3 p.Arg156Gln 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-ala475asp (accessed [today's date]).

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