Is CLIC2 p.Lys141Arg (c.422A>G) pathogenic?

CLIC2 p.Lys141Arg (c.422A>G) is classified Likely benign in CLIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely benign (0.0577); Absent from gnomAD v4.1.

How common is CLIC2 p.Lys141Arg (c.422A>G) in the general population?

CLIC2 p.Lys141Arg (c.422A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLIC2 p.Lys141Arg (c.422A>G)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

CLIC2 p.Lys141Arg

c.422A>G · VCV3833979

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.85 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.052	GERP -3.3, phastCons 0.94
Regional constraint	o/e 0.82	unconstrained · MANE · 57 kb · p 0.013 · regional, not allelic
Overall
CADD	12.65	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

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: CLIC2
Protein: p.Lys141Arg
Coding: c.422A>G
MANE Select: NM_001289
Type: single nucleotide variant
Location: chrX:155279309 (GRCh38)
Structure: AlphaFold pLDDT 93.28 · 3 PDB
Residue 141: the gst c-terminal domain; an α-helix; the 'c-terminal' region

Full CLIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC2 c.57+10C>T Benign/Likely benign ★★ same type
CLIC2 c.*19= Benign ★★ same type
CLIC2 p.Pro160Ala Benign/Likely benign ★★ same type
CLIC2 c.582+6T>C Uncertain significance ★ same type
CLIC2 p.Ala131Thr Uncertain significance ★ ⚠ same type
CLIC2 p.Arg170Gly Uncertain significance ★ ⚠ same type
CLIC2 p.Arg214His Conflicting classifications of pathogenicity ★ ⚠ same type
CLIC2 p.Arg222Cys Uncertain significance ★ ⚠ 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/clic2-p-lys141arg (accessed [today's date]).

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