Is GLS p.Pro67Ala (c.199C>G) pathogenic?

GLS p.Pro67Ala (c.199C>G) is classified Uncertain significance in GLS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.0609); Absent from gnomAD v4.1.

How common is GLS p.Pro67Ala (c.199C>G) in the general population?

GLS p.Pro67Ala (c.199C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLS p.Pro67Ala (c.199C>G)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

GLS p.Pro67Ala

c.199C>G · VCV4959143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.36	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 2.2	GERP 0.28, phastCons 0.47
Overall
CADD	13.38	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

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: GLS
Protein: p.Pro67Ala
Coding: c.199C>G
MANE Select: NM_014905
Type: single nucleotide variant
Location: chr2:190881283 (GRCh38)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 67: the 'disordered' region

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

Similar variants

GLS2 p.Gly67Asp Uncertain significance ★ ⚠ same residue
GLS p.Ala99Thr Uncertain significance ★★ ⚠ same type
GLS p.Leu25Arg Uncertain significance ★★ ⚠ same type
GLS c.387-3T>C Likely benign ★★ same type
GLS p.Ala561= Benign ★★ same type
GLS p.Arg53= Likely benign ★★ same type
GLS p.Pro313= Likely benign ★★ same type
GLS p.Val554= Likely benign ★★ 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/gls-p-pro67ala (accessed [today's date]).

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