Is CLCN2 p.Ala686Val (c.2057C>T) pathogenic?

CLCN2 p.Ala686Val (c.2057C>T) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-07). AlphaMissense: likely benign (0.0791); Very rare (popmax 0.00549%, sas); Associated with leukoencephalopathy with mild cerebellar ataxia and white matter edema.

What condition is associated with CLCN2 p.Ala686Val (c.2057C>T)?

CLCN2 p.Ala686Val (c.2057C>T) is associated with leukoencephalopathy with mild cerebellar ataxia and white matter edema, familial hyperaldosteronism type II, epilepsy, idiopathic generalized, susceptibility to, 11 (ClinVar).

How common is CLCN2 p.Ala686Val (c.2057C>T) in the general population?

CLCN2 p.Ala686Val (c.2057C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CLCN2 p.Ala686Val (c.2057C>T)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

CLCN2 p.Ala686Val

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.2057C>T · rs199641673 · VCV3145406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with mild cerebellar ataxia and white matter edema

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.36	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 2.9	GERP 0.46, phastCons 0.3
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	14.68	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 0.00549% South Asian · 5/91,088 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000991% 16/1,614,160 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,813
South Asiangrpmax	0.00549%	18,218
East Asian	0.00446%	22,433
European (non-Finnish)	8.47e-05%	1,180,027

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala686Val
Coding: c.2057C>T
MANE Select: NM_004366
dbSNP: rs199641673
Type: single nucleotide variant
Location: chr3:184353119 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 686: the 'disordered' region

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

Also linked: familial hyperaldosteronism type II epilepsy, idiopathic generalized, susceptibility to, 11

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

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

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
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-ala686val (accessed [today's date]).

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