Is GUSB p.Ala8Asp (c.23C>A) pathogenic?

GUSB p.Ala8Asp (c.23C>A) is classified Uncertain significance in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.332); Ultra-rare (popmax 0.0183%, mid); Associated with Inborn genetic diseases.

What condition is associated with GUSB p.Ala8Asp (c.23C>A)?

GUSB p.Ala8Asp (c.23C>A) is associated with Inborn genetic diseases (ClinVar).

How common is GUSB p.Ala8Asp (c.23C>A) in the general population?

GUSB p.Ala8Asp (c.23C>A) is ultra-rare (popmax 0.0183%, mid) (gnomAD).

What do computational predictors say about GUSB p.Ala8Asp (c.23C>A)?

AlphaMissense predicts likely benign (score 0.332) — an in-silico prediction, not a clinical call.

GUSB p.Ala8Asp

c.23C>A · VCV3523455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.332	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -11.73	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,069 bp · p 0.83 · regional, not allelic
Overall
CADD	7.69	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 0.0183% Middle Eastern · 1/5,456 alleles

Overall 7.31e-05% 1/1,367,866 alleles · ultra-rare

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: GUSB
Protein: p.Ala8Asp
Coding: c.23C>A
MANE Select: NM_000181
Type: single nucleotide variant
Location: chr7:65982161 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB

Full GUSB 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

Similar variants

GUSB p.Ala8Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
GUSB p.Ala8= Likely benign ★★ same residue
GUSB p.Ala8Thr Uncertain significance ★ ⚠ same residue
GUSB p.Ala380Thr Uncertain significance ★★ ⚠ same condition
GUSB p.Arg116His Uncertain significance ★★ ⚠ same condition
GUSB p.Arg57Gly Uncertain significance ★★ ⚠ same condition
GUSB p.Asn254His Uncertain significance ★★ ⚠ same condition
GUSB p.His509Gln Uncertain significance ★★ ⚠ 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/gusb-p-ala8asp (accessed [today's date]).

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