Is GLS p.Pro96Ser (c.286C>T) pathogenic?

GLS p.Pro96Ser (c.286C>T) is classified Uncertain significance in GLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.0611); Ultra-rare (popmax 0.0613%, amr); Associated with GLS-related disorder.

What condition is associated with GLS p.Pro96Ser (c.286C>T)?

GLS p.Pro96Ser (c.286C>T) is associated with GLS-related disorder (ClinVar).

How common is GLS p.Pro96Ser (c.286C>T) in the general population?

GLS p.Pro96Ser (c.286C>T) is ultra-rare (popmax 0.0613%, amr) (gnomAD).

What do computational predictors say about GLS p.Pro96Ser (c.286C>T)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

GLS p.Pro96Ser

c.286C>T · rs889058089 · VCV2634709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GLS-related disorder

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.32	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 3.5	GERP 1.2, phastCons 1
Overall
CADD	20.3	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 0.0613% Admixed American · 31/50,540 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0386%

Overall 0.00201% 31/1,539,486 alleles · ultra-rare exomes 28/1,387,428 · genomes 3/152,058 · joint denominator

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: GLS
Protein: p.Pro96Ser
Coding: c.286C>T
MANE Select: NM_014905
dbSNP: rs889058089
Type: single nucleotide variant
Location: chr2:190881370 (GRCh38)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 96: a turn

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

Disease context

GLS-related disorder

Similar variants

GLS p.Gln549Ter Pathogenic ★ same condition
GLS c.1650+1116A>C Uncertain significance ★ same condition
GLS p.Ser77Ala Uncertain significance ⚠ same condition
GLS c.1650+1093A>G Likely benign same condition
GLS c.1650+8A>C Benign same condition
GLS p.Ala51= Likely benign same condition
GLS p.Gly42Glu Likely benign same condition
GLS p.His89Pro Benign 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/gls-p-pro96ser (accessed [today's date]).

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