Is AP4B1 p.Ile669= (c.2007C>T) pathogenic?

AP4B1 p.Ile669= (c.2007C>T) is classified Likely benign in AP4B1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-29). Ultra-rare (popmax 0.0253%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Ile669= (c.2007C>T)?

AP4B1 p.Ile669= (c.2007C>T) is associated with Inborn genetic diseases, hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Ile669= (c.2007C>T) in the general population?

AP4B1 p.Ile669= (c.2007C>T) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

AP4B1 p.Ile669=

c.2007C>T · rs146869083 · VCV772016

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4.8
Overall
CADD	1.914	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% African / African-American · 19/75,060 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00328% 53/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,951
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Finnishnot grpmax-eligible	0.00312%	32,015
European (non-Finnish)	0.00153%	65,557
South Asian	0.0011%	91,088

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: AP4B1
Protein: p.Ile669=
Coding: c.2007C>T
MANE Select: NM_001253852
dbSNP: rs146869083
Type: single nucleotide variant
Location: chr1:113895278 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB
Residue 669: a β-strand; the 'ear; mediates interaction with tepsin' region

Full AP4B1 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

Also linked: hereditary spastic paraplegia 47

Similar variants

AP4B1 c.114-2A>C Pathogenic ★★ same condition
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 p.Arg102Ter Pathogenic ★★ same condition
AP4B1 p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg393Ter Pathogenic ★★ same condition
AP4B1 p.Arg406Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg514Ter Pathogenic/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/ap4b1-p-ile669 (accessed [today's date]).

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