Is CLCN3 p.Val324Ala (c.971T>C) pathogenic?

CLCN3 p.Val324Ala (c.971T>C) is classified Likely pathogenic in CLCN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9271); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and brain abnormalities.

What condition is associated with CLCN3 p.Val324Ala (c.971T>C)?

CLCN3 p.Val324Ala (c.971T>C) is associated with neurodevelopmental disorder with hypotonia and brain abnormalities (ClinVar).

How common is CLCN3 p.Val324Ala (c.971T>C) in the general population?

CLCN3 p.Val324Ala (c.971T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN3 p.Val324Ala (c.971T>C)?

AlphaMissense predicts likely pathogenic (score 0.9271) — an in-silico prediction, not a clinical call.

CLCN3 p.Val324Ala

c.971T>C · rs2150254146 · VCV1192288

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9271 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.9271	likely pathogenic ✓ concordant with ClinVar
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 12 kb · p 1.5e-15 · regional, not allelic
Overall
CADD	28.6	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: CLCN3
Protein: p.Val324Ala
Coding: c.971T>C
MANE Select: NM_001829
dbSNP: rs2150254146
Type: single nucleotide variant
Location: chr4:169695646 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB
Residue 324: a UniProt-annotated variant site (in nedhyba); an α-helix

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.Ile607Val Likely pathogenic ★★ ⚠ same condition
CLCN3 p.Thr570Ile 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
CLCN3 p.Ser453Arg Likely pathogenic ★ same condition
CLCN3 p.Thr438Ser Likely 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-val324ala (accessed [today's date]).

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