Is CLIC1 p.Pro200Ser (c.598C>T) pathogenic?

CLIC1 p.Pro200Ser (c.598C>T) is classified Uncertain significance in CLIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.8935); Very rare (popmax 8.47e-05%, nfe).

How common is CLIC1 p.Pro200Ser (c.598C>T) in the general population?

CLIC1 p.Pro200Ser (c.598C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLIC1 p.Pro200Ser (c.598C>T)?

AlphaMissense predicts likely pathogenic (score 0.8935) — an in-silico prediction, not a clinical call.

CLIC1 p.Pro200Ser

c.598C>T · VCV4003631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8935	likely pathogenic
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -10.96	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 5,455 bp · p 0.00014 · regional, not allelic
Overall
CADD	29.5	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 6.85e-05% 1/1,460,674 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.Pro200Ser
Coding: c.598C>T
MANE Select: NM_001288
Type: single nucleotide variant
Location: chr6:31730970 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.34 · 18 PDB
Residue 200: the gst c-terminal domain

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

Similar variants

CLIC1 p.Ala157Asp Uncertain significance ★ ⚠ same type
CLIC1 p.Arg204Pro 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-pro200ser (accessed [today's date]).

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