Is AP3D1 p.Asp196Glu (c.588C>A) pathogenic?

AP3D1 p.Asp196Glu (c.588C>A) is classified Uncertain significance in AP3D1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.7334); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with AP3D1 p.Asp196Glu (c.588C>A)?

AP3D1 p.Asp196Glu (c.588C>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP3D1 p.Asp196Glu (c.588C>A) in the general population?

AP3D1 p.Asp196Glu (c.588C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AP3D1 p.Asp196Glu (c.588C>A)?

AlphaMissense predicts likely pathogenic (score 0.7334) — an in-silico prediction, not a clinical call.

AP3D1 p.Asp196Glu

c.588C>A · rs768237900 · VCV1406604

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7334 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7334	likely pathogenic
REVEL	0.154	moderately benign-leaning
SaProt	LLR -11.57	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -1.1, phastCons 0.76
Regional constraint	o/e 0.71	unconstrained · MANE · 28 kb · p 3.4e-09 · regional, not allelic
Overall
CADD	19.43	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00118% 19/1,613,956 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0134%	7,480
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000678%	147,502

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: AP3D1
Protein: p.Asp196Glu
Coding: c.588C>A
MANE Select: NM_001261826
dbSNP: rs768237900
Type: single nucleotide variant
Location: chr19:2130412 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB

Full AP3D1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP3D1 p.Asp196Asn Uncertain significance ★ ⚠ same residue
AP3D1 p.Asp196= Likely benign ★ same residue
AP3D1 c.856+3G>A Uncertain significance ★★ same condition
AP3D1 p.Ala1076Val Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala247Val Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala285Ser Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala299Thr Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala438Thr 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/ap3d1-p-asp196glu (accessed [today's date]).

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