Is CLIC3 p.Arg191Cys (c.571C>T) pathogenic?

CLIC3 p.Arg191Cys (c.571C>T) is classified Uncertain significance in CLIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.273); Very rare (popmax 0.000516%, nfe).

How common is CLIC3 p.Arg191Cys (c.571C>T) in the general population?

CLIC3 p.Arg191Cys (c.571C>T) is very rare (popmax 0.000516%, nfe) (gnomAD).

What do computational predictors say about CLIC3 p.Arg191Cys (c.571C>T)?

AlphaMissense predicts likely benign (score 0.273) — an in-silico prediction, not a clinical call.

CLIC3 p.Arg191Cys

c.571C>T · VCV4654374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000516%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.273	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -11.70	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,859 bp · p 0.23 · regional, not allelic
Overall
CADD	29.8	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

Grpmax group 0.000516% European (non-Finnish) · 6/1,162,460 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000421% 6/1,423,668 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CLIC3
Protein: p.Arg191Cys
Coding: c.571C>T
MANE Select: NM_004669
Type: single nucleotide variant
Location: chr9:136994821 (GRCh38)
Gene constraint: LOEUF 1.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 2 PDB
Residue 191: an α-helix; the gst c-terminal domain

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.Arg200His Uncertain significance ★ ⚠ same type
CLIC3 p.Arg204Ser Uncertain significance ★ ⚠ same type
CLIC3 p.Arg27Gln Uncertain significance ★ ⚠ same type
CLIC3 p.Cys22Tyr 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-arg191cys (accessed [today's date]).

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