Is CLCN4 p.Arg306Lys (c.917G>A) pathogenic?

CLCN4 p.Arg306Lys (c.917G>A) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: ambiguous (0.4449); Absent from gnomAD v4.1.

How common is CLCN4 p.Arg306Lys (c.917G>A) in the general population?

CLCN4 p.Arg306Lys (c.917G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN4 p.Arg306Lys (c.917G>A)?

AlphaMissense predicts ambiguous (score 0.4449) — an in-silico prediction, not a clinical call.

CLCN4 p.Arg306Lys

c.917G>A · rs2518885315 · VCV2043469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4449 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4449	ambiguous
REVEL	0.736	pathogenic-leaning
SaProt	LLR -7.71	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 1,460 bp · p 1.7e-09 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN4
Protein: p.Arg306Lys
Coding: c.917G>A
MANE Select: NM_001830
dbSNP: rs2518885315
Type: single nucleotide variant
Location: chrX:10208118 (GRCh38)
Structure: AlphaFold pLDDT 84.66

Full CLCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN4 c.844-1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN4 p.Ala555Val Pathogenic ★★ same type
CLCN4 p.Arg718Trp Pathogenic ★★ same type
CLCN4 p.Asp89Asn Pathogenic/Likely pathogenic ★★ same type
CLCN4 p.Gly467Ser Likely pathogenic ★★ same type
CLCN4 p.Gly544Arg Pathogenic ★★ same type
CLCN4 p.Gly731Arg Pathogenic ★★ same type
CLCN4 p.Val275Met 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/clcn4-p-arg306lys (accessed [today's date]).

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