Is CLIC2 p.Arg5Gln (c.14G>A) pathogenic?

CLIC2 p.Arg5Gln (c.14G>A) is classified Uncertain significance in CLIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.1169); Very rare (popmax 0.00352%, sas).

How common is CLIC2 p.Arg5Gln (c.14G>A) in the general population?

CLIC2 p.Arg5Gln (c.14G>A) is very rare (popmax 0.00352%, sas) (gnomAD).

What do computational predictors say about CLIC2 p.Arg5Gln (c.14G>A)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

CLIC2 p.Arg5Gln

c.14G>A · rs1557323108 · VCV2623060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.34	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 0.21	GERP 0.81, phastCons 0.001
Regional constraint	o/e 0.82	unconstrained · MANE · 57 kb · p 0.013 · regional, not allelic
Overall
CADD	10.19	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 0.00352% South Asian · 2/56,811 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.00058% 7/1,207,758 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00352%	28,406
European (non-Finnish)	0.00056%	178,621

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: CLIC2
Protein: p.Arg5Gln
Coding: c.14G>A
MANE Select: NM_001289
dbSNP: rs1557323108
Type: single nucleotide variant
Location: chrX:155334414 (GRCh38)
Structure: AlphaFold pLDDT 93.28 · 3 PDB
Residue 5: the 'required for insertion into the membrane' region; the 'n-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-arg5gln (accessed [today's date]).

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