Is APBB2 p.Arg423Cys (c.1267C>T) pathogenic?

APBB2 p.Arg423Cys (c.1267C>T) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.9512); Very rare (popmax 0.00223%, eas).

How common is APBB2 p.Arg423Cys (c.1267C>T) in the general population?

APBB2 p.Arg423Cys (c.1267C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about APBB2 p.Arg423Cys (c.1267C>T)?

AlphaMissense predicts likely pathogenic (score 0.9512) — an in-silico prediction, not a clinical call.

APBB2 p.Arg423Cys

c.1267C>T · VCV4117776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9512	likely pathogenic
REVEL	0.633	indeterminate
SaProt	LLR -11.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R422C vs ClinVar R423C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,750 alleles

Overall 0.000186% 3/1,611,308 alleles · very rare exomes 3/1,459,052 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,750
Remaining individualsnot grpmax-eligible	0.0016%	62,388
European (non-Finnish)	8.48e-05%	1,178,600

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: APBB2
Protein: p.Arg423Cys
Coding: c.1267C>T
MANE Select: NM_004307
Type: single nucleotide variant
Location: chr4:40893399 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 422 UniProt numbering: the pid 1 domain

Full APBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB2 c.20-6C>T Benign ★★ same type
APBB2 p.Ala111Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala126Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala197Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala224Asp Uncertain significance ★ ⚠ same type
APBB2 p.Ala279Val Uncertain significance ★ same type
APBB2 p.Ala436Pro Uncertain significance ★ ⚠ same type
APBB2 p.Ala436Thr 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/apbb2-p-arg423cys (accessed [today's date]).

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