Is CLCN2 p.Arg68His (c.203G>A) pathogenic?

CLCN2 p.Arg68His (c.203G>A) is classified Benign/Likely benign in CLCN2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1109); Low-frequency (popmax 1.85%, afr); Associated with leukoencephalopathy with mild cerebellar ataxia and white matter edema.

What condition is associated with CLCN2 p.Arg68His (c.203G>A)?

CLCN2 p.Arg68His (c.203G>A) is associated with leukoencephalopathy with mild cerebellar ataxia and white matter edema (ClinVar).

How common is CLCN2 p.Arg68His (c.203G>A) in the general population?

CLCN2 p.Arg68His (c.203G>A) is low-frequency (popmax 1.85%, afr) (gnomAD).

What do computational predictors say about CLCN2 p.Arg68His (c.203G>A)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg68His

Q: How is Leukoencephalopathy with mild cerebellar ataxia and white matter edema inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.203G>A · rs61729156 · VCV217769

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.85%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

leukoencephalopathy with mild cerebellar ataxia and white matter edema

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -0.92, phastCons 0.03
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	24.2	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 1.85% African / African-American · 1,389/75,048 alleles

Filtering AF 1.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.74%

Overall 0.105% 1,692/1,613,586 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.85%	54
Middle Eastern	0.215%	466
Remaining individualsnot grpmax-eligible	0.142%	702
Admixed American	0.118%	846
East Asian	0.0111%	8,978
European (non-Finnish)	0.0101%	9,916
South Asian	0.00659%	15,182

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.Arg68His
Coding: c.203G>A
MANE Select: NM_004366
dbSNP: rs61729156
Type: single nucleotide variant
Location: chr3:184358992 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 68: a UniProt-annotated variant site (reduces channel activity)

Full CLCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with mild cerebellar ataxia and white matter edema — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukoencephalopathy with mild cerebellar ataxia and white matter edema (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CLCN2 p.Arg68Cys 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.Trp570Ter Pathogenic/Likely pathogenic ★★ same condition
CLCN2 c.1171-3T>C Uncertain significance ★★ same condition
CLCN2 c.1721+4C>T Uncertain significance ★★ same condition
CLCN2 c.1721+5G>A 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-arg68his (accessed [today's date]).

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