Is CLCN3 p.Arg418= (c.1254C>T) pathogenic?

CLCN3 p.Arg418= (c.1254C>T) is classified Likely benign in CLCN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). Very rare (popmax 0.000205%).

How common is CLCN3 p.Arg418= (c.1254C>T) in the general population?

CLCN3 p.Arg418= (c.1254C>T) is very rare (popmax 0.000205%) (gnomAD).

CLCN3 p.Arg418=

c.1254C>T · VCV4534974

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000205%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.009	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -0.88, phastCons 0.99
Overall
CADD	11.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000205%

Overall 0.000205% 3/1,461,888 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: CLCN3
Protein: p.Arg418=
Coding: c.1254C>T
MANE Select: NM_001829
Type: single nucleotide variant
Location: chr4:169697425 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB
Residue 418: an α-helix

Full CLCN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN3 p.Arg418Cys Uncertain significance ★ ⚠ same residue
CLCN3 p.Arg418Pro Uncertain significance ★ ⚠ same residue
CLCN3 p.Ile607Val Likely pathogenic ★★ ⚠ same type
CLCN3 p.Thr570Ile Likely pathogenic ★★ ⚠ same type
CLCN3 p.Val324Ala Likely pathogenic ★★ same type
CLCN3 c.2367-2099A>C Uncertain significance ★★ same type
CLCN3 p.Asn788Ser Uncertain significance ★★ ⚠ same type
CLCN3 p.Asp485Asn 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/clcn3-p-arg418 (accessed [today's date]).

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