Is CLIC3 p.Ala2Val (c.5C>T) pathogenic?

CLIC3 p.Ala2Val (c.5C>T) is classified Uncertain significance in CLIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.2167); Very rare (popmax 0.0024%, eas).

How common is CLIC3 p.Ala2Val (c.5C>T) in the general population?

CLIC3 p.Ala2Val (c.5C>T) is very rare (popmax 0.0024%, eas) (gnomAD).

What do computational predictors say about CLIC3 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2167) — an in-silico prediction, not a clinical call.

CLIC3 p.Ala2Val

c.5C>T · VCV4229853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0024%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2167	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,859 bp · p 0.23 · regional, not allelic
Overall
CADD	26.5	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 0.0024% East Asian · 1/41,604 alleles

Overall 7.13e-05% 1/1,401,938 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.Ala2Val
Coding: c.5C>T
MANE Select: NM_004669
Type: single nucleotide variant
Location: chr9:136996539 (GRCh38)
Gene constraint: LOEUF 1.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 2 PDB
Residue 2: the 'required for insertion into the membrane' region

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.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
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-ala2val (accessed [today's date]).

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