Is AP4E1 p.Arg304Ter (c.910C>T) pathogenic?

AP4E1 p.Arg304Ter (c.910C>T) is classified Pathogenic/Likely pathogenic in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). Very rare (popmax 0.00267%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Arg304Ter (c.910C>T)?

AP4E1 p.Arg304Ter (c.910C>T) is associated with Spastic paraplegia, congenital nervous system disorder (ClinVar).

How common is AP4E1 p.Arg304Ter (c.910C>T) in the general population?

AP4E1 p.Arg304Ter (c.910C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

AP4E1 p.Arg304Ter

c.910C>T · rs569567659 · VCV1180640

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 21
Splicing
SpliceAI	Δ0.21	donor loss · deltas
Pangolin	Δ0.36	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.4	GERP 1.7, phastCons 1
Overall
CADD	36.0	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 0.00267% African / African-American · 2/74,826 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000435% 7/1,608,318 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,413
Finnishnot grpmax-eligible	0.00156%	63,952
South Asian	0.0011%	90,876
European (non-Finnish)	0.000255%	391,779

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.Arg304Ter
Coding: c.910C>T
MANE Select: NM_007347
dbSNP: rs569567659
Type: single nucleotide variant
Location: chr15:50934664 (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

Also linked: congenital nervous system disorder

Similar variants

AP4E1 p.Arg304Gly Uncertain significance ★ ⚠ same residue
AP4E1 p.Arg304Gln Uncertain significance ★★ ⚠ same residue
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

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-arg304ter (accessed [today's date]).

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