Is CLCN5 p.Ser322Phe (c.965C>T) pathogenic?

CLCN5 p.Ser322Phe (c.965C>T) is classified Uncertain significance in CLCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1.

How common is CLCN5 p.Ser322Phe (c.965C>T) in the general population?

CLCN5 p.Ser322Phe (c.965C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN5 p.Ser322Phe (c.965C>T)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CLCN5 p.Ser322Phe

c.965C>T · VCV3665446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 5% in CLCN5
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -14.30	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 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 12 kb · p 1.3e-15 · regional, not allelic
Overall
CADD	30.0	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: CLCN5
Protein: p.Ser322Phe
Coding: c.965C>T
MANE Select: NM_001127898
Type: single nucleotide variant
Location: chrX:50086011 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB

Full CLCN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN5 c.1014+1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN5 c.604-1G>C Likely pathogenic ★★ same type
CLCN5 c.933+1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg417Ter Pathogenic ★★ same type
CLCN5 p.Arg537Ter Pathogenic ★★ same type
CLCN5 p.Arg586Trp Pathogenic/Likely pathogenic ★★ same type
CLCN5 p.Arg707Ter Pathogenic ★★ 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/clcn5-p-ser322phe (accessed [today's date]).

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