Is AP4B1 p.Thr59Ala (c.175A>G) pathogenic?

AP4B1 p.Thr59Ala (c.175A>G) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.4835); Ultra-rare (popmax 0.0133%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Thr59Ala (c.175A>G)?

AP4B1 p.Thr59Ala (c.175A>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Thr59Ala (c.175A>G) in the general population?

AP4B1 p.Thr59Ala (c.175A>G) is ultra-rare (popmax 0.0133%, nfe) (gnomAD).

What do computational predictors say about AP4B1 p.Thr59Ala (c.175A>G)?

AlphaMissense predicts ambiguous (score 0.4835) — an in-silico prediction, not a clinical call.

AP4B1 p.Thr59Ala

c.175A>G · rs151293980 · VCV472194

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4835 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4835	ambiguous
REVEL	0.068	moderately benign-leaning
SaProt	LLR -9.81	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% European (non-Finnish) · 157/1,180,048 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0103% 167/1,614,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0133%	7,516
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Finnishnot grpmax-eligible	0.00625%	16,009
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00133%	74,928

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.Thr59Ala
Coding: c.175A>G
MANE Select: NM_001253852
dbSNP: rs151293980
Type: single nucleotide variant
Location: chr1:113902801 (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 p.Thr59Ser Uncertain significance ★★ ⚠ same residue
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

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-thr59ala (accessed [today's date]).

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