Is AP4B1 p.Cys73Ser (c.217T>A) pathogenic?

AP4B1 p.Cys73Ser (c.217T>A) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-17). AlphaMissense: ambiguous (0.4936); Rare (popmax 0.243%, amr); Associated with hereditary spastic paraplegia 47.

What condition is associated with AP4B1 p.Cys73Ser (c.217T>A)?

AP4B1 p.Cys73Ser (c.217T>A) is associated with hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Cys73Ser (c.217T>A) in the general population?

AP4B1 p.Cys73Ser (c.217T>A) is rare (popmax 0.243%, amr) (gnomAD).

What do computational predictors say about AP4B1 p.Cys73Ser (c.217T>A)?

AlphaMissense predicts ambiguous (score 0.4936) — an in-silico prediction, not a clinical call.

AP4B1 p.Cys73Ser

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.217T>A · rs552888524 · VCV240688

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4936 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.243%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary spastic paraplegia 47

Computational evidence

Protein change
AlphaMissense	0.4936	ambiguous
REVEL	0.154	moderately benign-leaning
SaProt	LLR -5.39	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 6.7	GERP 0.96, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	20.2	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 0.243% Admixed American · 146/60,020 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.00929% 150/1,614,230 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.243%	411
Remaining individualsnot grpmax-eligible	0.0032%	31,255
African / African-American	0.00266%	37,527

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.Cys73Ser
Coding: c.217T>A
MANE Select: NM_001253852
dbSNP: rs552888524
Type: single nucleotide variant
Location: chr1:113902759 (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.Cys73Ter Pathogenic ★ same residue
AP4B1 p.Cys73= Likely benign ★ 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-cys73ser (accessed [today's date]).

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