Is CLCN6 p.Cys495Phe (c.1484G>T) pathogenic?

CLCN6 p.Cys495Phe (c.1484G>T) is classified Uncertain significance in CLCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-25). AlphaMissense: ambiguous (0.4613); Absent from gnomAD v4.1.

How common is CLCN6 p.Cys495Phe (c.1484G>T) in the general population?

CLCN6 p.Cys495Phe (c.1484G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN6 p.Cys495Phe (c.1484G>T)?

AlphaMissense predicts ambiguous (score 0.4613) — an in-silico prediction, not a clinical call.

CLCN6 p.Cys495Phe

c.1484G>T · rs2523153928 · VCV2717198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4613 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4613	ambiguous
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -9.05	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 34 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	29.6	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: CLCN6
Protein: p.Cys495Phe
Coding: c.1484G>T
MANE Select: NM_001286
dbSNP: rs2523153928
Type: single nucleotide variant
Location: chr1:11833988 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 3 PDB
Residue 495: an α-helix

Full CLCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN6 p.Tyr553Cys Pathogenic ★★ same type
CLCN6 p.Ala127Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala144Glu Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala256Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala392Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala527Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala78Val 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/clcn6-p-cys495phe (accessed [today's date]).

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