Is AP3B2 p.Arg1042Ser (c.3124C>A) pathogenic?

AP3B2 p.Arg1042Ser (c.3124C>A) is classified Likely benign in AP3B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.6867); Very rare (popmax 0.00127%, nfe).

How common is AP3B2 p.Arg1042Ser (c.3124C>A) in the general population?

AP3B2 p.Arg1042Ser (c.3124C>A) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about AP3B2 p.Arg1042Ser (c.3124C>A)?

AlphaMissense predicts likely pathogenic (score 0.6867) — an in-silico prediction, not a clinical call.

AP3B2 p.Arg1042Ser

c.3124C>A · rs184339082 · VCV1556557

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6867	likely pathogenic
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.47	donor gain · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,925 bp · p 0.51 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1023S vs ClinVar R1042S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,878 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.0177% 285/1,613,968 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.414%	242
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)grpmax	0.00127%	78,658

Finnish 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: AP3B2
Protein: p.Arg1042Ser
Coding: c.3124C>A
MANE Select: NM_001278512
dbSNP: rs184339082
Type: single nucleotide variant
Location: chr15:82659876 (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.Arg1042His Conflicting classifications of pathogenicity ★ ⚠ same residue
AP3B2 p.Arg1042= Likely benign ★ 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-arg1042ser (accessed [today's date]).

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