Is CLCN7 p.Val596Ile (c.1786G>A) pathogenic?

CLCN7 p.Val596Ile (c.1786G>A) is classified Conflicting classifications of pathogenicity in CLCN7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.0671); Ultra-rare (popmax 0.0423%, eas); Associated with Inborn genetic diseases.

What condition is associated with CLCN7 p.Val596Ile (c.1786G>A)?

CLCN7 p.Val596Ile (c.1786G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN7 p.Val596Ile (c.1786G>A) in the general population?

CLCN7 p.Val596Ile (c.1786G>A) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

What do computational predictors say about CLCN7 p.Val596Ile (c.1786G>A)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

CLCN7 p.Val596Ile

c.1786G>A · rs200121444 · VCV1910710

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.25	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 3.3	GERP 0.27, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 1.8e-09 · regional, not allelic
Overall
CADD	20.2	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 0.0423% East Asian · 19/44,876 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00304% 49/1,612,636 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0423%	2,362
Admixed American	0.00833%	12,004
South Asian	0.0022%	45,544
European (non-Finnish)	0.00178%	56,191
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	75,042

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: CLCN7
Protein: p.Val596Ile
Coding: c.1786G>A
MANE Select: NM_001287
dbSNP: rs200121444
Type: single nucleotide variant
Location: chr16:1448977 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 596: an α-helix

Full CLCN7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN7 p.Ala131Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala259Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala464Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala673Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala714Thr Uncertain significance ★★ same condition
CLCN7 p.Arg223Trp Uncertain significance ★★ ⚠ same condition
CLCN7 p.Arg25Gln Uncertain significance ★★ ⚠ same condition

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/clcn7-p-val596ile (accessed [today's date]).

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