Is AP4B1 p.Arg449Ter (c.1345A>T) pathogenic?

AP4B1 p.Arg449Ter (c.1345A>T) is classified Pathogenic in AP4B1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-03). Very rare (popmax 0.00801%, afr); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Arg449Ter (c.1345A>T)?

AP4B1 p.Arg449Ter (c.1345A>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Arg449Ter (c.1345A>T) in the general population?

AP4B1 p.Arg449Ter (c.1345A>T) is very rare (popmax 0.00801%, afr) (gnomAD).

AP4B1 p.Arg449Ter

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.1345A>T · rs142209254 · VCV521444

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

hereditary spastic paraplegia 47

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.34	loss · gain 0.02 · independent
Constraint at this position
Conservation	phyloP 1.6	GERP 1.3, phastCons 0.031
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,940 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000434% 7/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,490
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg449Ter
Coding: c.1345A>T
dbSNP: rs142209254
Type: single nucleotide variant
Location: chr1:113896423 (GRCh38)

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

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-arg449ter (accessed [today's date]).

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