Is CLCN2 p.Arg66Trp (c.196C>T) pathogenic?

CLCN2 p.Arg66Trp (c.196C>T) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1463); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Arg66Trp (c.196C>T)?

CLCN2 p.Arg66Trp (c.196C>T) is associated with Inborn genetic diseases, familial hyperaldosteronism type II, epilepsy, idiopathic generalized, susceptibility to, 11 (ClinVar).

How common is CLCN2 p.Arg66Trp (c.196C>T) in the general population?

CLCN2 p.Arg66Trp (c.196C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CLCN2 p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg66Trp

c.196C>T · rs777420720 · VCV2516052

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -10.11	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	26.4	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 0.00329% South Asian · 3/91,096 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,613,488 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,365
African / African-American	0.00267%	37,465
European (non-Finnish)	0.00127%	78,670

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: CLCN2
Protein: p.Arg66Trp
Coding: c.196C>T
MANE Select: NM_004366
dbSNP: rs777420720
Type: single nucleotide variant
Location: chr3:184358999 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB

Full CLCN2 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

Also linked: familial hyperaldosteronism type II epilepsy, idiopathic generalized, susceptibility to, 11 leukoencephalopathy with mild cerebellar ataxia and white matter edema

Similar variants

CLCN2 p.Arg66Gln Uncertain significance ★★ ⚠ same residue
CLCN2 c.898+1G>A Likely pathogenic ★★ same condition
CLCN2 p.Arg172Gln Pathogenic ★★ same condition
CLCN2 p.Arg610Ter Pathogenic/Likely pathogenic ★★ same condition
CLCN2 p.Gly24Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLCN2 p.Trp570Ter Pathogenic/Likely pathogenic ★★ same condition
CLCN2 c.1171-3T>C Uncertain significance ★★ same condition
CLCN2 c.1721+4C>T 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/clcn2-p-arg66trp (accessed [today's date]).

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