Is CLCN6 p.Arg55Cys (c.163C>T) pathogenic?

CLCN6 p.Arg55Cys (c.163C>T) is classified Uncertain significance in CLCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-21). AlphaMissense: likely benign (0.1483); Ultra-rare (popmax 0.0164%, mid).

How common is CLCN6 p.Arg55Cys (c.163C>T) in the general population?

CLCN6 p.Arg55Cys (c.163C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CLCN6 p.Arg55Cys (c.163C>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

CLCN6 p.Arg55Cys

c.163C>T · rs1570519033 · VCV1901185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.502	indeterminate
SaProt	LLR -5.85	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 34 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	25.5	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000992% 16/1,613,494 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00134%	74,890
European (non-Finnish)	0.00119%	84,261

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: CLCN6
Protein: p.Arg55Cys
Coding: c.163C>T
MANE Select: NM_001286
dbSNP: rs1570519033
Type: single nucleotide variant
Location: chr1:11815861 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 3 PDB

Full CLCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN6 p.Arg55Gly Uncertain significance ★ ⚠ same residue
CLCN6 p.Arg55His Uncertain significance ★ ⚠ same residue
CLCN6 p.Tyr553Cys Pathogenic ★★ ⚠ same type
CLCN6 p.Ala127Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala144Glu Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala256Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala392Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala522Thr 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/clcn6-p-arg55cys (accessed [today's date]).

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