Is GLS p.Ser77Ala (c.229T>G) pathogenic?

GLS p.Ser77Ala (c.229T>G) is classified Uncertain significance in GLS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.0636); Very rare (popmax 0.000796%, nfe); Associated with GLS-related disorder.

What condition is associated with GLS p.Ser77Ala (c.229T>G)?

GLS p.Ser77Ala (c.229T>G) is associated with GLS-related disorder (ClinVar).

How common is GLS p.Ser77Ala (c.229T>G) in the general population?

GLS p.Ser77Ala (c.229T>G) is very rare (popmax 0.000796%, nfe) (gnomAD).

What do computational predictors say about GLS p.Ser77Ala (c.229T>G)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

GLS p.Ser77Ala

c.229T>G · rs1367964499 · VCV3032963

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000796%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GLS-related disorder

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -5.63	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 5.5	GERP 1.2, phastCons 1
Overall
CADD	19.9	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 0.000796% European (non-Finnish) · 9/1,130,706 alleles

Filtering AF 0.000375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000271%

Overall 0.000595% 9/1,512,132 alleles · very rare exomes 7/1,360,610 · genomes 2/151,522 · 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.Ser77Ala
Coding: c.229T>G
MANE Select: NM_014905
dbSNP: rs1367964499
Type: single nucleotide variant
Location: chr2:190881313 (GRCh38)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 77: an α-helix

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

Disease context

GLS-related disorder

Similar variants

GLS p.Ser77Pro Uncertain significance ★ ⚠ same residue
GLS p.Ser77= Likely benign ★ same residue
GLS p.Gln549Ter Pathogenic ★ same condition
GLS c.1650+1116A>C Uncertain significance ★ same condition
GLS p.Pro96Ser 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

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-ser77ala (accessed [today's date]).

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