Is CLIC2 p.Pro100Thr (c.298C>A) pathogenic?

CLIC2 p.Pro100Thr (c.298C>A) is classified Uncertain significance in CLIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). AlphaMissense: ambiguous (0.5343); Ultra-rare (popmax 0.0194%, afr).

How common is CLIC2 p.Pro100Thr (c.298C>A) in the general population?

CLIC2 p.Pro100Thr (c.298C>A) is ultra-rare (popmax 0.0194%, afr) (gnomAD).

What do computational predictors say about CLIC2 p.Pro100Thr (c.298C>A)?

AlphaMissense predicts ambiguous (score 0.5343) — an in-silico prediction, not a clinical call.

CLIC2 p.Pro100Thr

c.298C>A · VCV3833977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5343 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5343	ambiguous
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -8.03	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.99, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 57 kb · p 0.013 · regional, not allelic
Overall
CADD	24.7	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 0.0194% African / African-American · 11/56,659 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00837%

Overall 0.000929% 11/1,183,554 alleles · ultra-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: CLIC2
Protein: p.Pro100Thr
Coding: c.298C>A
MANE Select: NM_001289
Type: single nucleotide variant
Location: chrX:155280064 (GRCh38)
Structure: AlphaFold pLDDT 93.28 · 3 PDB
Residue 100: the gst c-terminal domain; the 'joint loop' region

Full CLIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC2 c.57+10C>T Benign/Likely benign ★★ same type
CLIC2 c.*19= Benign ★★ same type
CLIC2 p.Pro160Ala Benign/Likely benign ★★ same type
CLIC2 c.582+6T>C Uncertain significance ★ same type
CLIC2 p.Ala131Thr Uncertain significance ★ ⚠ same type
CLIC2 p.Arg170Gly Uncertain significance ★ ⚠ same type
CLIC2 p.Arg214His Conflicting classifications of pathogenicity ★ ⚠ same type
CLIC2 p.Arg222Cys 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/clic2-p-pro100thr (accessed [today's date]).

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