Is GLS p.Arg70Pro (c.209G>C) pathogenic?

GLS p.Arg70Pro (c.209G>C) is classified Uncertain significance in GLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.1015); Very rare (popmax 0.000373%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GLS p.Arg70Pro (c.209G>C)?

GLS p.Arg70Pro (c.209G>C) is associated with Inborn genetic diseases (ClinVar).

How common is GLS p.Arg70Pro (c.209G>C) in the general population?

GLS p.Arg70Pro (c.209G>C) is very rare (popmax 0.000373%, nfe) (gnomAD).

What do computational predictors say about GLS p.Arg70Pro (c.209G>C)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

GLS p.Arg70Pro

c.209G>C · VCV4030287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -9.88	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 1.1	GERP 0.32, phastCons 0.75
Overall
CADD	19.76	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 0.000373% European (non-Finnish) · 4/1,071,980 alleles

Filtering AF 8.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.9e-05%

Overall 0.00032% 4/1,249,768 alleles · very rare

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.Arg70Pro
Coding: c.209G>C
MANE Select: NM_013267 · reported on NM_014905
Type: single nucleotide variant
Location: chr2:190881293 (GRCh38)
Structure: AlphaFold pLDDT 85.66 · 4 PDB

Full GLS 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

GLS p.Arg70Trp Uncertain significance ★ ⚠ same residue
GLS p.Ala99Thr Uncertain significance ★★ ⚠ same condition
GLS p.Leu25Arg Uncertain significance ★★ ⚠ same condition
GLS p.Arg570Gln Likely pathogenic ★ same condition
GLS p.Ala23Thr Uncertain significance ★ ⚠ same condition
GLS p.Ala28Thr Uncertain significance ★ ⚠ same condition
GLS p.Ala50Asp Uncertain significance ★ ⚠ same condition
GLS p.Ala50Thr 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/gls-p-arg70pro (accessed [today's date]).

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