Is AP4E1 p.Val430= (c.1290C>T) pathogenic?

AP4E1 p.Val430= (c.1290C>T) is classified Likely benign in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). Ultra-rare (popmax 0.0329%, mid); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Val430= (c.1290C>T)?

AP4E1 p.Val430= (c.1290C>T) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Val430= (c.1290C>T) in the general population?

AP4E1 p.Val430= (c.1290C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

AP4E1 p.Val430=

c.1290C>T · rs767875770 · VCV1628290

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP -1.1, phastCons 1
Overall
CADD	11.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00254% 41/1,613,720 alleles · ultra-rare exomes 38/1,461,592 · genomes 3/152,128 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
Admixed American	0.00833%	11,999
European (non-Finnish)	0.00254%	39,331
South Asian	0.0022%	45,526
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,886

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: AP4E1
Protein: p.Val430=
Coding: c.1290C>T
MANE Select: NM_007347
dbSNP: rs767875770
Type: single nucleotide variant
Location: chr15:50948133 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB

Full AP4E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala45Thr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala475Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Arg646Cys Uncertain significance ★★ same condition
AP4E1 p.Asn1086Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp484Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp938Gly Uncertain significance ★★ ⚠ 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/ap4e1-p-val430 (accessed [today's date]).

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