Is AP3B2 p.Arg99Cys (c.295C>T) pathogenic?

AP3B2 p.Arg99Cys (c.295C>T) is classified Uncertain significance in AP3B2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9807); Very rare (popmax 0.00178%, nfe); Associated with developmental and epileptic encephalopathy, 48.

What condition is associated with AP3B2 p.Arg99Cys (c.295C>T)?

AP3B2 p.Arg99Cys (c.295C>T) is associated with developmental and epileptic encephalopathy, 48 (ClinVar).

How common is AP3B2 p.Arg99Cys (c.295C>T) in the general population?

AP3B2 p.Arg99Cys (c.295C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about AP3B2 p.Arg99Cys (c.295C>T)?

AlphaMissense predicts likely pathogenic (score 0.9807) — an in-silico prediction, not a clinical call.

AP3B2 p.Arg99Cys

c.295C>T · rs373196064 · VCV1696933

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 48

Computational evidence

Protein change
AlphaMissense	0.9807	likely pathogenic
REVEL	0.376	indeterminate
SaProt	LLR -13.06	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 Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 0.92, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 29 kb · p 3.5e-16 · regional, not allelic
Overall
CADD	34.0	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 0.00178% European (non-Finnish) · 21/1,179,462 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00149% 24/1,612,714 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,993
European (non-Finnish)grpmax	0.00178%	56,165
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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.Arg99Cys
Coding: c.295C>T
MANE Select: NM_001278512
dbSNP: rs373196064
Type: single nucleotide variant
Location: chr15:82688801 (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

Disease context

developmental and epileptic encephalopathy, 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP3B2 p.Arg99Ser Uncertain significance ★ ⚠ same residue
AP3B2 p.Arg977Ter Pathogenic ★★ same condition
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same condition
AP3B2 c.1110+3G>C Uncertain significance ★★ same condition
AP3B2 p.Ala1098Asp Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala546Pro Uncertain significance ★★ ⚠ same condition
AP3B2 p.Arg977Gln Uncertain significance ★★ ⚠ same condition
AP3B2 p.Asn552Tyr Uncertain significance ★★ ⚠ same condition

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-arg99cys (accessed [today's date]).

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