Is CLCN4 p.Val455Ile (c.1363G>A) pathogenic?

CLCN4 p.Val455Ile (c.1363G>A) is classified Benign in CLCN4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.061); Rare (popmax 0.157%, eas).

How common is CLCN4 p.Val455Ile (c.1363G>A) in the general population?

CLCN4 p.Val455Ile (c.1363G>A) is rare (popmax 0.157%, eas) (gnomAD).

What do computational predictors say about CLCN4 p.Val455Ile (c.1363G>A)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

CLCN4 p.Val455Ile

c.1363G>A · rs369733340 · VCV696075

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP -0.019, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 4,468 bp · p 3.1e-10 · regional, not allelic
Overall
CADD	13.27	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

Grpmax group 0.157% East Asian · 53/33,660 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.00821% 99/1,206,344 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.157%	635
Remaining individualsnot grpmax-eligible	0.0379%	2,641
Ashkenazi Jewishnot grpmax-eligible	0.0091%	10,987
African / African-American	0.00527%	18,967
South Asian	0.00353%	28,306
European (non-Finnish)	0.00235%	42,579

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: CLCN4
Protein: p.Val455Ile
Coding: c.1363G>A
MANE Select: NM_001830
dbSNP: rs369733340
Type: single nucleotide variant
Location: chrX:10208564 (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-val455ile (accessed [today's date]).

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