Is AP3B2 p.Pro993fs (c.2978_2979del) pathogenic?

AP3B2 p.Pro993fs (c.29782979del) is classified Pathogenic/Likely pathogenic in AP3B2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-05-04). Very rare (popmax 0.0022%, sas); Associated with developmental and epileptic encephalopathy, 48.

What condition is associated with AP3B2 p.Pro993fs (c.2978_2979del)?

AP3B2 p.Pro993fs (c.2978_2979del) is associated with developmental and epileptic encephalopathy, 48 (ClinVar).

How common is AP3B2 p.Pro993fs (c.2978_2979del) in the general population?

AP3B2 p.Pro993fs (c.2978_2979del) is very rare (popmax 0.0022%, sas) (gnomAD).

AP3B2 p.Pro993fs

c.2978_2979del · rs1347618037 · VCV987398

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

developmental and epileptic encephalopathy, 48

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 25 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 1.9, phastCons 0.92
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,996 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,722 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asiangrpmax	0.0022%	45,498
European (non-Finnish)	0.000763%	131,096

Remaining individuals 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.Pro993fs
Coding: c.2978_2979del
MANE Select: NM_001278512
dbSNP: rs1347618037
Type: Deletion
Location: chr15:82661862 (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.Tyr94fs Pathogenic/Likely pathogenic ★★ same condition
AP3B2 p.Pro993= Likely benign ★★ same residue
AP3B2 c.2262-34_2268del Likely pathogenic ★ same condition
AP3B2 p.Glu152fs Likely pathogenic ★ same condition
AP3B2 p.Glu613fs Pathogenic ★ same condition
AP3B2 p.Leu131del Likely pathogenic ★ same condition
AP3B2 p.Leu224_Cys225insTer Likely pathogenic ★ same condition
AP3B2 p.Tyr376_Leu377insTer Likely pathogenic ★ 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-pro993fs (accessed [today's date]).

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