Is AP4B1 p.Ala674Ser (c.2020G>T) pathogenic?

AP4B1 p.Ala674Ser (c.2020G>T) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.0822); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Ala674Ser (c.2020G>T)?

AP4B1 p.Ala674Ser (c.2020G>T) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Ala674Ser (c.2020G>T) in the general population?

AP4B1 p.Ala674Ser (c.2020G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AP4B1 p.Ala674Ser (c.2020G>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

AP4B1 p.Ala674Ser

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.2020G>T · rs769479430 · VCV1059290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 47

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -4.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.48	gain · loss 0.00 · independent
Constraint at this position
Conservation	phyloP -0.36	GERP -4.4
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	9.491	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00137% 20/1,461,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.000932%	107,276

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.Ala674Ser
Coding: c.2020G>T
dbSNP: rs769479430
Type: single nucleotide variant
Location: chr1:113895265 (GRCh38)

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

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-ala674ser (accessed [today's date]).

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