Is CLCN3 p.Tyr207Cys (c.620A>G) pathogenic?

CLCN3 p.Tyr207Cys (c.620A>G) is classified Uncertain significance in CLCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely pathogenic (0.8964); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CLCN3 p.Tyr207Cys (c.620A>G)?

CLCN3 p.Tyr207Cys (c.620A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN3 p.Tyr207Cys (c.620A>G) in the general population?

CLCN3 p.Tyr207Cys (c.620A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN3 p.Tyr207Cys (c.620A>G)?

AlphaMissense predicts likely pathogenic (score 0.8964) — an in-silico prediction, not a clinical call.

CLCN3 p.Tyr207Cys

c.620A>G · rs1732328265 · VCV3145418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8964	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -14.92	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 12 kb · p 8.6e-14 · regional, not allelic
Overall
CADD	29.5	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.Tyr207Cys
Coding: c.620A>G
MANE Select: NM_001829
dbSNP: rs1732328265
Type: single nucleotide variant
Location: chr4:169690543 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB
Residue 207: 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 p.Tyr207Asp Uncertain significance ★ ⚠ same residue
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

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-tyr207cys (accessed [today's date]).

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