Is AP4B1 p.Ile125Val (c.373A>G) pathogenic?

AP4B1 p.Ile125Val (c.373A>G) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-11). AlphaMissense: likely benign (0.0821); Ultra-rare (popmax 0.0333%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Ile125Val (c.373A>G)?

AP4B1 p.Ile125Val (c.373A>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Ile125Val (c.373A>G) in the general population?

AP4B1 p.Ile125Val (c.373A>G) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about AP4B1 p.Ile125Val (c.373A>G)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

AP4B1 p.Ile125Val

c.373A>G · rs143769705 · VCV1003759

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -6.05	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 -0.17	GERP -1.6, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	12.35	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 0.0333% African / African-American · 25/75,044 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00167% 27/1,614,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,002
East Asian	0.00223%	44,888
European (non-Finnish)	8.47e-05%	1,180,013

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: AP4B1
Protein: p.Ile125Val
Coding: c.373A>G
MANE Select: NM_001253852
dbSNP: rs143769705
Type: single nucleotide variant
Location: chr1:113901851 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 47

Similar variants

AP4B1 c.114-2A>C Pathogenic ★★ same condition
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 p.Arg102Ter Pathogenic ★★ same condition
AP4B1 p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg393Ter Pathogenic ★★ same condition
AP4B1 p.Arg406Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg514Ter Pathogenic/Likely pathogenic ★★ 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/ap4b1-p-ile125val (accessed [today's date]).

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