Is AP4E1 p.Ala475Val (c.1424C>T) pathogenic?

AP4E1 p.Ala475Val (c.1424C>T) is classified Uncertain significance in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-19). AlphaMissense: likely benign (0.3178); Rare (popmax 0.123%, sas); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ala475Val (c.1424C>T)?

AP4E1 p.Ala475Val (c.1424C>T) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Ala475Val (c.1424C>T) in the general population?

AP4E1 p.Ala475Val (c.1424C>T) is rare (popmax 0.123%, sas) (gnomAD).

What do computational predictors say about AP4E1 p.Ala475Val (c.1424C>T)?

AlphaMissense predicts likely benign (score 0.3178) — an in-silico prediction, not a clinical call.

AP4E1 p.Ala475Val

c.1424C>T · rs200678853 · VCV434240

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3178 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.3178	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	27.6	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 0.123% South Asian · 112/91,002 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0976%

Overall 0.0114% 183/1,610,696 alleles · rare exomes 169/1,458,604 · genomes 14/152,092 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.123%	813
Middle Eastern	0.115%	867
East Asian	0.0357%	2,798
African / African-American	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.00481%	20,799
Admixed American	0.00333%	29,995
European (non-Finnish)	0.0028%	35,673

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.Ala475Val
Coding: c.1424C>T
MANE Select: NM_007347
dbSNP: rs200678853
Type: single nucleotide variant
Location: chr15:50949933 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 475: a UniProt-annotated variant site (in stut1; uncertain significance)

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.Ala475= Likely benign ★ same residue
AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala45Thr 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-ala475val (accessed [today's date]).

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