Is AP4B1 p.Ser134= (c.402A>C) pathogenic?

AP4B1 p.Ser134= (c.402A>C) is classified Benign in AP4B1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). Common (popmax 6.67%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Ser134= (c.402A>C)?

AP4B1 p.Ser134= (c.402A>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 47, hereditary spastic paraplegia (ClinVar).

AP4B1 p.Ser134=

Q: How common is AP4B1 p.Ser134= (c.402A>C) in the general population?

AP4B1 p.Ser134= (c.402A>C) is common (popmax 6.67%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.402A>C · rs34751342 · VCV157722

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 6.67%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -4.2
Overall
CADD	1.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.67% South Asian · 6,077/91,080 alleles

Filtering AF 6.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.47%

Overall 3.93% 63,501/1,614,146 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	7.86%	13
South Asiangrpmax	6.67%	15
Middle Eastern	4.26%	23
European (non-Finnish)	4.14%	24
Remaining individualsnot grpmax-eligible	4.05%	25
Amishnot grpmax-eligible	3.84%	26
Finnishnot grpmax-eligible	2.72%	37
Admixed American	1.9%	53
African / African-American	0.66%	152
East Asian	0.0267%	3,740

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser134=
Coding: c.402A>C
MANE Select: NM_001253852
dbSNP: rs34751342
Type: single nucleotide variant
Location: chr1:113901822 (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 hereditary spastic paraplegia

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-ser134 (accessed [today's date]).

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