Is CLCN3 p.Ile511Met (c.1533C>G) pathogenic?

CLCN3 p.Ile511Met (c.1533C>G) is classified Uncertain significance in CLCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1192); Ultra-rare (popmax 0.0147%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLCN3 p.Ile511Met (c.1533C>G)?

CLCN3 p.Ile511Met (c.1533C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN3 p.Ile511Met (c.1533C>G) in the general population?

CLCN3 p.Ile511Met (c.1533C>G) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about CLCN3 p.Ile511Met (c.1533C>G)?

AlphaMissense predicts likely benign (score 0.1192) — an in-silico prediction, not a clinical call.

CLCN3 p.Ile511Met

c.1533C>G · rs779627892 · VCV2603956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1192	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -6.62	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 1	GERP 0.038, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 12 kb · p 1.5e-15 · regional, not allelic
Overall
CADD	17.36	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 0.0147% African / African-American · 11/74,914 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000807% 13/1,611,288 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,810
Admixed American	0.00333%	29,985

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: CLCN3
Protein: p.Ile511Met
Coding: c.1533C>G
MANE Select: NM_001829
dbSNP: rs779627892
Type: single nucleotide variant
Location: chr4:169697704 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB
Residue 511: an α-helix

Full CLCN3 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

CLCN3 c.2367-2099A>C Uncertain significance ★★ same condition
CLCN3 p.Asn788Ser Uncertain significance ★★ ⚠ same condition
CLCN3 p.Pro465Thr Uncertain significance ★★ ⚠ same condition
CLCN3 p.Tyr342Ser Uncertain significance ★★ ⚠ same condition
CLCN3 p.Ser453Ile Likely pathogenic ★ same condition
CLCN3 c.2367-2056A>C Uncertain significance ★ same condition
CLCN3 c.607-2A>C Uncertain significance ★ same condition
CLCN3 c.*39G>T 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/clcn3-p-ile511met (accessed [today's date]).

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