Is AP3B2 p.Arg458Cys (c.1372C>T) pathogenic?

AP3B2 p.Arg458Cys (c.1372C>T) is classified Uncertain significance in AP3B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-11). AlphaMissense: likely pathogenic (0.6842); Very rare (popmax 0.00235%, eas).

How common is AP3B2 p.Arg458Cys (c.1372C>T) in the general population?

AP3B2 p.Arg458Cys (c.1372C>T) is very rare (popmax 0.00235%, eas) (gnomAD).

What do computational predictors say about AP3B2 p.Arg458Cys (c.1372C>T)?

AlphaMissense predicts likely pathogenic (score 0.6842) — an in-silico prediction, not a clinical call.

AP3B2 p.Arg458Cys

c.1372C>T · rs1397996908 · VCV2111790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00235%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6842	likely pathogenic
REVEL	0.3	indeterminate
SaProt	LLR -13.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP -3.5, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 15 kb · p 1.1e-11 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00235% East Asian · 1/42,586 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000428% 6/1,401,914 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00235%	42,586
Remaining individualsnot grpmax-eligible	0.00166%	60,256
European (non-Finnish)	0.000348%	287,391

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: AP3B2
Protein: p.Arg458Cys
Coding: c.1372C>T
MANE Select: NM_001278512
dbSNP: rs1397996908
Type: single nucleotide variant
Location: chr15:82677677 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 75.73

Full AP3B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3B2 p.Arg458His Uncertain significance ★ ⚠ same residue
AP3B2 p.Arg458Leu Uncertain significance ★ same residue
AP3B2 c.114-1G>A Likely pathogenic ★★ same type
AP3B2 p.Arg977Ter Pathogenic ★★ same type
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same type
AP3B2 c.1110+3G>C Uncertain significance ★★ same type
AP3B2 c.1853-5C>A Uncertain significance ★★ same type
AP3B2 c.2834-3C>A 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/ap3b2-p-arg458cys (accessed [today's date]).

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