Is CLIC3 p.Pro220Thr (c.658C>A) pathogenic?

CLIC3 p.Pro220Thr (c.658C>A) is classified Uncertain significance in CLIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely pathogenic (0.6827); Absent from gnomAD v4.1.

How common is CLIC3 p.Pro220Thr (c.658C>A) in the general population?

CLIC3 p.Pro220Thr (c.658C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLIC3 p.Pro220Thr (c.658C>A)?

AlphaMissense predicts likely pathogenic (score 0.6827) — an in-silico prediction, not a clinical call.

CLIC3 p.Pro220Thr

c.658C>A · VCV3833982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6827 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6827	likely pathogenic
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -10.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.59	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,859 bp · p 0.23 · regional, not allelic
Overall
CADD	24.6	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: CLIC3
Protein: p.Pro220Thr
Coding: c.658C>A
MANE Select: NM_004669
Type: single nucleotide variant
Location: chr9:136994734 (GRCh38)
Gene constraint: LOEUF 1.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 2 PDB
Residue 220: the gst c-terminal domain; an α-helix

Full CLIC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC3 p.Ala151Val Uncertain significance ★ ⚠ same type
CLIC3 p.Ala188Thr Uncertain significance ★ ⚠ same type
CLIC3 p.Ala209Thr Uncertain significance ★ ⚠ same type
CLIC3 p.Ala2Val Uncertain significance ★ ⚠ same type
CLIC3 p.Arg191Cys Uncertain significance ★ ⚠ same type
CLIC3 p.Arg200His Uncertain significance ★ ⚠ same type
CLIC3 p.Arg204Ser Uncertain significance ★ ⚠ same type
CLIC3 p.Arg27Gln 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/clic3-p-pro220thr (accessed [today's date]).

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