Is GUSB p.Arg57Trp (c.169C>T) pathogenic?

GUSB p.Arg57Trp (c.169C>T) is classified Uncertain significance in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1521); Very rare (popmax 0.00937%, afr); Associated with Inborn genetic diseases.

What condition is associated with GUSB p.Arg57Trp (c.169C>T)?

GUSB p.Arg57Trp (c.169C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GUSB p.Arg57Trp (c.169C>T) in the general population?

GUSB p.Arg57Trp (c.169C>T) is very rare (popmax 0.00937%, afr) (gnomAD).

What do computational predictors say about GUSB p.Arg57Trp (c.169C>T)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

GUSB p.Arg57Trp

c.169C>T · VCV4268105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00937%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP -1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,069 bp · p 0.83 · regional, not allelic
Overall
CADD	24.1	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 0.00937% African / African-American · 7/74,678 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.000497% 8/1,609,872 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00937%	10,668
European (non-Finnish)	8.48e-05%	1,179,350

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.Arg57Trp
Coding: c.169C>T
MANE Select: NM_000181
Type: single nucleotide variant
Location: chr7:65982015 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB
Residue 57: an α-helix

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.Arg57Gly Uncertain significance ★★ ⚠ same residue
GUSB p.Arg57Gln Likely benign ★ same residue
GUSB p.Arg57Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GUSB p.Ala380Thr Uncertain significance ★★ ⚠ same condition
GUSB p.Arg116His Uncertain significance ★★ ⚠ same condition
GUSB p.Asn254His Uncertain significance ★★ ⚠ same condition
GUSB p.His509Gln Uncertain significance ★★ ⚠ same condition
GUSB p.Lys606Glu 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-arg57trp (accessed [today's date]).

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