Is CLCN5 p.Ser558Arg (c.1674C>G) pathogenic?

CLCN5 p.Ser558Arg (c.1674C>G) is classified Uncertain significance in CLCN5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.2648); Very rare (popmax 0.00351%, sas).

How common is CLCN5 p.Ser558Arg (c.1674C>G) in the general population?

CLCN5 p.Ser558Arg (c.1674C>G) is very rare (popmax 0.00351%, sas) (gnomAD).

What do computational predictors say about CLCN5 p.Ser558Arg (c.1674C>G)?

AlphaMissense predicts likely benign (score 0.2648) — an in-silico prediction, not a clinical call.

CLCN5 p.Ser558Arg

c.1674C>G · rs2147601639 · VCV1309466

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2648	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -7.58	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 0.54	GERP 1.2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 12 kb · p 1.3e-15 · regional, not allelic
Overall
CADD	21.3	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 0.00351% South Asian · 2/56,970 alleles

Filtering AF 0.000582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000182% 2/1,097,852 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: CLCN5
Protein: p.Ser558Arg
Coding: c.1674C>G
MANE Select: NM_001127898
dbSNP: rs2147601639
Type: single nucleotide variant
Location: chrX:50088814 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB

Full CLCN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN5 c.1014+1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN5 c.604-1G>C Likely pathogenic ★★ same type
CLCN5 c.933+1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg417Ter Pathogenic ★★ same type
CLCN5 p.Arg537Ter Pathogenic ★★ same type
CLCN5 p.Arg586Trp Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg707Ter Pathogenic ★★ 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/clcn5-p-ser558arg (accessed [today's date]).

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