Is AP4B1 p.Ala595= (c.1785C>T) pathogenic?

AP4B1 p.Ala595= (c.1785C>T) is classified Likely benign in AP4B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). Very rare (popmax 0.00769%, sas); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Ala595= (c.1785C>T)?

AP4B1 p.Ala595= (c.1785C>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Ala595= (c.1785C>T) in the general population?

AP4B1 p.Ala595= (c.1785C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

AP4B1 p.Ala595=

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.1785C>T · VCV3671033

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

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 -0.24	GERP -4
Overall
CADD	1.781	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,078 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00161% 26/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
African / African-American	0.00534%	18,722
European (non-Finnish)	0.00127%	78,669

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.Ala595=
Coding: c.1785C>T
MANE Select: NM_001253852
Type: single nucleotide variant
Location: chr1:113895764 (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 595: the 'hinge' region

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-ala595 (accessed [today's date]).

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