Is AP4E1 p.Lys258Arg (c.773A>G) pathogenic?

AP4E1 p.Lys258Arg (c.773A>G) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: likely benign (0.0996); Very rare (popmax 0.00133%, afr); Associated with hereditary spastic paraplegia 51.

What condition is associated with AP4E1 p.Lys258Arg (c.773A>G)?

AP4E1 p.Lys258Arg (c.773A>G) is associated with hereditary spastic paraplegia 51 (ClinVar).

How common is AP4E1 p.Lys258Arg (c.773A>G) in the general population?

AP4E1 p.Lys258Arg (c.773A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Lys258Arg (c.773A>G)?

AlphaMissense predicts likely benign (score 0.0996) — an in-silico prediction, not a clinical call.

AP4E1 p.Lys258Arg

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.773A>G · rs2063826694 · VCV2582319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 51

Computational evidence

Protein change
AlphaMissense	0.0996	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -4.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Overall 6.84e-05% 1/1,461,848 alleles · very rare

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.Lys258Arg
Coding: c.773A>G
MANE Select: NM_007347
dbSNP: rs2063826694
Type: single nucleotide variant
Location: chr15:50930875 (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

hereditary spastic paraplegia 51 — 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

Similar variants

AP4E1 p.Lys258= Likely benign ★ same residue
AP4E1 p.Arg1105Ter Pathogenic ★★ same condition
AP4E1 p.His128Tyr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Lys181Gln Uncertain significance ★★ ⚠ same condition
AP4E1 p.Pro717Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr559Pro Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr911Ala Uncertain significance ★★ ⚠ same condition
AP4E1 c.1066+51T>C Benign ★★ 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-lys258arg (accessed [today's date]).

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