Is GLS2 p.Arg166Cys (c.496C>T) pathogenic?

GLS2 p.Arg166Cys (c.496C>T) is classified Uncertain significance in GLS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). AlphaMissense: likely benign (0.1061); Ultra-rare (popmax 0.0164%, mid).

How common is GLS2 p.Arg166Cys (c.496C>T) in the general population?

GLS2 p.Arg166Cys (c.496C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about GLS2 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

GLS2 p.Arg166Cys

c.496C>T · rs776900455 · VCV3100352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 0.79, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 1,614 bp · p 2.3e-07 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,613,358 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Finnishnot grpmax-eligible	0.00157%	63,820
African / African-American	0.00134%	74,706
European (non-Finnish)	0.000509%	196,656

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.Arg166Cys
Coding: c.496C>T
MANE Select: NM_013267
dbSNP: rs776900455
Type: single nucleotide variant
Location: chr12:56479090 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 166: an α-helix

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

Similar variants

GLS2 p.Arg166His 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-arg166cys (accessed [today's date]).

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