Is CLCN3 p.Ser239Phe (c.716C>T) pathogenic?

CLCN3 p.Ser239Phe (c.716C>T) is classified Uncertain significance in CLCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1.

How common is CLCN3 p.Ser239Phe (c.716C>T) in the general population?

CLCN3 p.Ser239Phe (c.716C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN3 p.Ser239Phe (c.716C>T)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

CLCN3 p.Ser239Phe

c.716C>T · VCV3342157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 7% in CLCN3
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -14.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 12 kb · p 8.6e-14 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Ser239Phe
Coding: c.716C>T
MANE Select: NM_001829
Type: single nucleotide variant
Location: chr4:169690639 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB
Residue 239: a binding site

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

Similar variants

CLCN3 p.Ile607Val Likely pathogenic ★★ same type
CLCN3 p.Thr570Ile Likely pathogenic ★★ ⚠ same type
CLCN3 p.Val324Ala Likely pathogenic ★★ same type
CLCN3 c.2367-2099A>C Uncertain significance ★★ same type
CLCN3 p.Asn788Ser Uncertain significance ★★ ⚠ same type
CLCN3 p.Asp485Asn Uncertain significance ★★ ⚠ same type
CLCN3 p.Lys186Glu Uncertain significance ★★ ⚠ same type
CLCN3 p.Pro465Thr Uncertain significance ★★ 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/clcn3-p-ser239phe (accessed [today's date]).

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