Is GUSB p.Leu565Val (c.1693C>G) pathogenic?

GUSB p.Leu565Val (c.1693C>G) is classified Uncertain significance in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0931); Very rare (popmax 8.48e-05%, nfe).

How common is GUSB p.Leu565Val (c.1693C>G) in the general population?

GUSB p.Leu565Val (c.1693C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GUSB p.Leu565Val (c.1693C>G)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

GUSB p.Leu565Val

c.1693C>G · VCV4535893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -4.64	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 -0.38	GERP -1.7
Regional constraint	o/e 0.75	unconstrained · MANE · 15 kb · p 3.7e-08 · regional, not allelic
Overall
CADD	0.446	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 8.48e-05% European (non-Finnish) · 1/1,178,762 alleles

Overall 6.86e-05% 1/1,458,514 alleles · very 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.Leu565Val
Coding: c.1693C>G
MANE Select: NM_000181
Type: single nucleotide variant
Location: chr7:65964419 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB
Residue 565: an α-helix

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

Similar variants

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GUSB c.581+1G>A Pathogenic/Likely pathogenic ★★ same type
GUSB c.724+1G>T Pathogenic/Likely pathogenic ★★ same type
GUSB p.Ala619Val Pathogenic/Likely pathogenic ★★ ⚠ same type
GUSB p.Arg110Ter Pathogenic/Likely pathogenic ★★ same type
GUSB p.Arg167Ter Pathogenic/Likely pathogenic ★★ same type
GUSB p.Arg216Trp Pathogenic/Likely pathogenic ★★ same type
GUSB p.Arg357Ter Pathogenic/Likely pathogenic ★★ same type

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-leu565val (accessed [today's date]).

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