Is CLIC1 p.Arg204Pro (c.611G>C) pathogenic?

CLIC1 p.Arg204Pro (c.611G>C) is classified Uncertain significance in CLIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely benign (0.293); Very rare (popmax 0.000254%, nfe).

How common is CLIC1 p.Arg204Pro (c.611G>C) in the general population?

CLIC1 p.Arg204Pro (c.611G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CLIC1 p.Arg204Pro (c.611G>C)?

AlphaMissense predicts likely benign (score 0.293) — an in-silico prediction, not a clinical call.

CLIC1 p.Arg204Pro

c.611G>C · rs373588470 · VCV2278342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.293	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.32, phastCons 0.98
Regional constraint	o/e 0.78	unconstrained · MANE · 5,455 bp · p 0.00014 · regional, not allelic
Overall
CADD	19.68	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,986 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,650 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: CLIC1
Protein: p.Arg204Pro
Coding: c.611G>C
MANE Select: NM_001288
dbSNP: rs373588470
Type: single nucleotide variant
Location: chr6:31730957 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.34 · 18 PDB
Residue 204: the gst c-terminal domain; an α-helix

Full CLIC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC1 p.Arg204Gln Likely benign ★ same residue
CLIC1 p.Ala157Asp Uncertain significance ★ ⚠ same type
CLIC1 p.Arg92Ser Uncertain significance ★ ⚠ same type
CLIC1 p.Glu234Lys Uncertain significance ★ ⚠ same type
CLIC1 p.Glu4Gly Uncertain significance ★ ⚠ same type
CLIC1 p.Glu9Lys Uncertain significance ★ ⚠ same type
CLIC1 p.Gly196Arg Uncertain significance ★ ⚠ same type
CLIC1 p.Gly61Val 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/clic1-p-arg204pro (accessed [today's date]).

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