Is CLIC4 p.Arg133Ser (c.399G>T) pathogenic?

CLIC4 p.Arg133Ser (c.399G>T) is classified Uncertain significance in CLIC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely pathogenic (0.8271); Absent from gnomAD v4.1.

How common is CLIC4 p.Arg133Ser (c.399G>T) in the general population?

CLIC4 p.Arg133Ser (c.399G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLIC4 p.Arg133Ser (c.399G>T)?

AlphaMissense predicts likely pathogenic (score 0.8271) — an in-silico prediction, not a clinical call.

CLIC4 p.Arg133Ser

c.399G>T · VCV3833987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8271 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8271	likely pathogenic
REVEL	0.531	indeterminate
SaProt	LLR -10.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP -0.39, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	23.5	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: CLIC4
Protein: p.Arg133Ser
Coding: c.399G>T
MANE Select: NM_013943
Type: single nucleotide variant
Location: chr1:24827100 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 3 PDB
Residue 133: the gst c-terminal domain

Full CLIC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC4 p.Arg206His Uncertain significance ★ ⚠ same type
CLIC4 p.Asn115Thr Uncertain significance ★ ⚠ same type
CLIC4 p.Asp209Asn Uncertain significance ★ ⚠ same type
CLIC4 p.Asp228Asn Uncertain significance ★ ⚠ same type
CLIC4 p.Glu183Gly Uncertain significance ★ ⚠ same type
CLIC4 p.Glu241Gly Uncertain significance ★ ⚠ same type
CLIC4 p.Gly181Ser Uncertain significance ★ ⚠ same type
CLIC4 p.Ile78Val 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/clic4-p-arg133ser (accessed [today's date]).

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