Is GUSB p.Val99Met (c.295G>A) pathogenic?

GUSB p.Val99Met (c.295G>A) is classified Uncertain significance in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2013-10-14). AlphaMissense: likely pathogenic (0.6437); Absent from gnomAD v4.1.

How common is GUSB p.Val99Met (c.295G>A) in the general population?

GUSB p.Val99Met (c.295G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GUSB p.Val99Met (c.295G>A)?

AlphaMissense predicts likely pathogenic (score 0.6437) — an in-silico prediction, not a clinical call.

GUSB p.Val99Met

c.295G>A · rs398123237 · VCV92590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6437 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6437	likely pathogenic
REVEL	0.756	pathogenic-leaning
SaProt	LLR -11.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,069 bp · p 0.83 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GUSB
Protein: p.Val99Met
Coding: c.295G>A
MANE Select: NM_000181
dbSNP: rs398123237
Type: single nucleotide variant
Location: chr7:65980325 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB
Residue 99: a β-strand

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

Similar variants

GUSB p.Val99= Likely benign ★ same residue
GUSB c.1244+1G>A Pathogenic ★★ same type
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

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-val99met (accessed [today's date]).

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