Is AP4B1 p.Arg107Trp (c.319C>T) pathogenic?

AP4B1 p.Arg107Trp (c.319C>T) is classified Conflicting classifications of pathogenicity in AP4B1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-02-02). AlphaMissense: likely pathogenic (0.9276); Very rare (popmax 0.00246%, nfe); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Arg107Trp (c.319C>T)?

AP4B1 p.Arg107Trp (c.319C>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Arg107Trp (c.319C>T) in the general population?

AP4B1 p.Arg107Trp (c.319C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about AP4B1 p.Arg107Trp (c.319C>T)?

AlphaMissense predicts likely pathogenic (score 0.9276) — an in-silico prediction, not a clinical call.

AP4B1 p.Arg107Trp

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.319C>T · rs74361335 · VCV828196

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 47

Computational evidence

Protein change
AlphaMissense	0.9276	likely pathogenic
REVEL	0.544	indeterminate
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	34.0	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 0.00246% European (non-Finnish) · 29/1,180,018 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,613,290 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,809
European (non-Finnish)grpmax	0.00246%	40,690
Admixed American	0.00167%	60,020
South Asian	0.0011%	91,030

Remaining individuals 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.Arg107Trp
Coding: c.319C>T
MANE Select: NM_001253852
dbSNP: rs74361335
Type: single nucleotide variant
Location: chr1:113902657 (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

hereditary spastic paraplegia 47 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4B1 p.Arg107Gln Uncertain significance ★ ⚠ same residue
AP4B1 p.Arg107Gly 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

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-arg107trp (accessed [today's date]).

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