Is AP4B1 p.Ile575= (c.1725C>T) pathogenic?

AP4B1 p.Ile575= (c.1725C>T) is classified Likely benign in AP4B1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-05). Rare (popmax 0.627%, mid); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Ile575= (c.1725C>T)?

AP4B1 p.Ile575= (c.1725C>T) is associated with hereditary spastic paraplegia 47, hereditary spastic paraplegia (ClinVar).

How common is AP4B1 p.Ile575= (c.1725C>T) in the general population?

AP4B1 p.Ile575= (c.1725C>T) is rare (popmax 0.627%, mid) (gnomAD).

AP4B1 p.Ile575=

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.1725C>T · rs34778731 · VCV588263

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.627%, mid)

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 2.2	GERP -3, phastCons 1
Overall
CADD	5.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.627% Middle Eastern · 38/6,062 alleles

Filtering AF 0.469% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.415%

Overall 0.0453% 731/1,614,258 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.627%	160
Ashkenazi Jewishnot grpmax-eligible	0.459%	218
Remaining individualsnot grpmax-eligible	0.096%	1,042
Admixed American	0.055%	1,819
European (non-Finnish)	0.036%	2,777
African / African-American	0.02%	5,005
Finnishnot grpmax-eligible	0.0187%	5,337
South Asian	0.0132%	7,591

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.Ile575=
Coding: c.1725C>T
MANE Select: NM_001253852
dbSNP: rs34778731
Type: single nucleotide variant
Location: chr1:113895824 (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 575: 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

Also linked: hereditary spastic paraplegia

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4B1 p.Ile575Ser Uncertain significance ★★ ⚠ same residue
AP4B1 p.Ile575Val Benign/Likely benign ★★ same residue
AP4B1 p.Ile575Thr Uncertain significance ★ ⚠ same residue
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

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-ile575 (accessed [today's date]).

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