Is GLS2 p.Arg107Pro (c.320G>C) pathogenic?

GLS2 p.Arg107Pro (c.320G>C) is classified Uncertain significance in GLS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.9941); Very rare (popmax 0.00229%, nfe).

How common is GLS2 p.Arg107Pro (c.320G>C) in the general population?

GLS2 p.Arg107Pro (c.320G>C) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about GLS2 p.Arg107Pro (c.320G>C)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

GLS2 p.Arg107Pro

c.320G>C · VCV4264347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic · top 4% in GLS2
REVEL	0.635	indeterminate
SaProt	LLR -16.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,307 bp · p 0.6 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00229% European (non-Finnish) · 27/1,179,978 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00174% 28/1,612,778 alleles · very rare exomes 26/1,460,704 · genomes 2/152,074 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,703
Remaining individualsnot grpmax-eligible	0.0016%	62,352

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: GLS2
Protein: p.Arg107Pro
Coding: c.320G>C
MANE Select: NM_013267
Type: single nucleotide variant
Location: chr12:56479864 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 107: an α-helix

Full GLS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLS2 p.Arg107Gln 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/gls2-p-arg107pro (accessed [today's date]).

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