Is AP4B1 p.Leu78= (c.232C>T) pathogenic?

AP4B1 p.Leu78= (c.232C>T) is classified Likely benign in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). Ultra-rare (popmax 0.02%, amr); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Leu78= (c.232C>T)?

AP4B1 p.Leu78= (c.232C>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Leu78= (c.232C>T) in the general population?

AP4B1 p.Leu78= (c.232C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

AP4B1 p.Leu78=

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.232C>T · rs760117027 · VCV1615926

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

hereditary spastic paraplegia 47

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 7.4	GERP 0.15, phastCons 1
Overall
CADD	11.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,026 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000889% 13/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Leu78=
Coding: c.232C>T
MANE Select: NM_001253852
dbSNP: rs760117027
Type: single nucleotide variant
Location: chr1:113902744 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 47 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-leu78 (accessed [today's date]).

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