Is AP4E1 p.Ile406Val (c.1216A>G) pathogenic?

AP4E1 p.Ile406Val (c.1216A>G) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely benign (0.0536); Very rare (popmax 0.00935%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ile406Val (c.1216A>G)?

AP4E1 p.Ile406Val (c.1216A>G) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Ile406Val (c.1216A>G) in the general population?

AP4E1 p.Ile406Val (c.1216A>G) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Ile406Val (c.1216A>G)?

AlphaMissense predicts likely benign (score 0.0536) — an in-silico prediction, not a clinical call.

AP4E1 p.Ile406Val

c.1216A>G · rs371779124 · VCV1396887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0536	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -5.49	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 0.36	GERP -3.4, phastCons 0.85
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	2.698	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 0.00935% African / African-American · 7/74,834 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00199% 32/1,610,250 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,691
Admixed American	0.00667%	15,001
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578
Remaining individualsnot grpmax-eligible	0.00321%	31,173
European (non-Finnish)	0.00153%	65,378

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.Ile406Val
Coding: c.1216A>G
MANE Select: NM_007347
dbSNP: rs371779124
Type: single nucleotide variant
Location: chr15:50948059 (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.Ile406Met Uncertain significance ★ ⚠ 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.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-ile406val (accessed [today's date]).

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