Is AP4B1 p.Val348= (c.1044G>A) pathogenic?

AP4B1 p.Val348= (c.1044G>A) is classified Conflicting classifications of pathogenicity in AP4B1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-10). Ultra-rare (popmax 0.0164%, mid); Associated with hereditary spastic paraplegia.

What condition is associated with AP4B1 p.Val348= (c.1044G>A)?

AP4B1 p.Val348= (c.1044G>A) is associated with hereditary spastic paraplegia, hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Val348= (c.1044G>A) in the general population?

AP4B1 p.Val348= (c.1044G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

AP4B1 p.Val348=

c.1044G>A · rs763730264 · VCV1336108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.24	GERP -0.64, phastCons 0.97
Overall
CADD	15.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00105% 17/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.00468%	21,346
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00102%	98,331

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.Val348=
Coding: c.1044G>A
dbSNP: rs763730264
Type: single nucleotide variant
Location: chr1:113899974 (GRCh38)

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

Disease context

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

Also linked: hereditary spastic paraplegia 47

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-val348 (accessed [today's date]).

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