Is AP5Z1 p.Arg792His (c.2375G>A) pathogenic?

AP5Z1 p.Arg792His (c.2375G>A) is classified Conflicting classifications of pathogenicity in AP5Z1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.0777); Ultra-rare (popmax 0.0537%, eas); Associated with hereditary spastic paraplegia 48.

What condition is associated with AP5Z1 p.Arg792His (c.2375G>A)?

AP5Z1 p.Arg792His (c.2375G>A) is associated with hereditary spastic paraplegia 48, hereditary spastic paraplegia (ClinVar).

How common is AP5Z1 p.Arg792His (c.2375G>A) in the general population?

AP5Z1 p.Arg792His (c.2375G>A) is ultra-rare (popmax 0.0537%, eas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 48 inherited?

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

What do computational predictors say about AP5Z1 p.Arg792His (c.2375G>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

AP5Z1 p.Arg792His

c.2375G>A · rs201677317 · VCV1080493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0537%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 48

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -2.9
Regional constraint	o/e 1.43	unconstrained · MANE · 16 kb · p 5.7e-46 · regional, not allelic
Overall
CADD	17.89	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 0.0537% East Asian · 24/44,728 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.0194% 313/1,609,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0537%	1,864
Middle Eastern	0.0331%	3,017
European (non-Finnish)	0.0223%	4,482
Remaining individualsnot grpmax-eligible	0.0144%	6,926
South Asian	0.00774%	12,927
African / African-American	0.00533%	18,755
Admixed American	0.00502%	19,907
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,492

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: AP5Z1
Protein: p.Arg792His
Coding: c.2375G>A
MANE Select: NM_014855
dbSNP: rs201677317
Type: single nucleotide variant
Location: chr7:4791336 (GRCh38)
Gene constraint: LOEUF 1.641 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.32

Full AP5Z1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 48 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

AP5Z1 p.Arg792Cys Uncertain significance ★★ ⚠ same residue
AP5Z1 c.1312-2A>G Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 c.1707+1G>A Likely pathogenic ★★ same condition
AP5Z1 c.1806-1G>C Likely pathogenic ★★ same condition
AP5Z1 p.Arg138Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg310Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg311Ter Pathogenic/Likely pathogenic ★★ same condition
AP5Z1 p.Arg345Ter 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/ap5z1-p-arg792his (accessed [today's date]).

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