Is CLCN3 p.Asn17Ser (c.50A>G) pathogenic?

CLCN3 p.Asn17Ser (c.50A>G) is classified Uncertain significance in CLCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-24). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0165%, mid); Associated with neurodevelopmental disorder with hypotonia and brain abnormalities.

What condition is associated with CLCN3 p.Asn17Ser (c.50A>G)?

CLCN3 p.Asn17Ser (c.50A>G) is associated with neurodevelopmental disorder with hypotonia and brain abnormalities (ClinVar).

How common is CLCN3 p.Asn17Ser (c.50A>G) in the general population?

CLCN3 p.Asn17Ser (c.50A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLCN3 p.Asn17Ser (c.50A>G)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

CLCN3 p.Asn17Ser

c.50A>G · VCV3376395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -5.51	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 9.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 44 kb · p 0.1 · regional, not allelic
Overall
CADD	22.1	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00164% 24/1,460,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.00195%	51,283

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.Asn17Ser
Coding: c.50A>G
MANE Select: NM_001829
Type: single nucleotide variant
Location: chr4:169635978 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB

Full CLCN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN3 p.Asn17Lys Uncertain significance ★ ⚠ same residue
CLCN3 p.Ile607Val Likely pathogenic ★★ ⚠ same condition
CLCN3 p.Thr570Ile Likely pathogenic ★★ ⚠ same condition
CLCN3 p.Val324Ala Likely pathogenic ★★ same condition
CLCN3 p.Asp87Val Likely pathogenic ★ same condition
CLCN3 p.Ile252Thr Likely pathogenic ★ same condition
CLCN3 p.Ile607Thr Likely pathogenic ★ same condition
CLCN3 p.Lys309Glu Pathogenic ★ 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-asn17ser (accessed [today's date]).

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