Is CLCN2 p.Ser811Pro (c.2431T>C) pathogenic?

CLCN2 p.Ser811Pro (c.2431T>C) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.9968); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Ser811Pro (c.2431T>C)?

CLCN2 p.Ser811Pro (c.2431T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Ser811Pro (c.2431T>C) in the general population?

CLCN2 p.Ser811Pro (c.2431T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CLCN2 p.Ser811Pro (c.2431T>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

CLCN2 p.Ser811Pro

c.2431T>C · rs2474222437 · VCV2813883

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 7% in CLCN2
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -15.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,044 alleles

Overall 6.84e-05% 1/1,461,704 alleles · very rare

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.Ser811Pro
Coding: c.2431T>C
MANE Select: NM_004366
dbSNP: rs2474222437
Type: single nucleotide variant
Location: chr3:184347006 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 811: an α-helix; the cbs 2 domain; a UniProt-annotated variant site (in lkpat; decreased voltage-gated chloride channel activity; does not affect protein expression; does not affect localization at the cell membrane)

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

Similar variants

CLCN2 p.Ala243Pro Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala253Val Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala638Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala70Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala717Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Arg297Gln Uncertain significance ★★ ⚠ same condition
CLCN2 p.Arg558Gln Uncertain significance ★★ ⚠ same condition
CLCN2 p.Arg598Gln 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-ser811pro (accessed [today's date]).

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