Is CLIC3 p.Val19Met (c.55G>A) pathogenic?

CLIC3 p.Val19Met (c.55G>A) is classified Uncertain significance in CLIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.2789); Ultra-rare (popmax 0.0429%, mid).

How common is CLIC3 p.Val19Met (c.55G>A) in the general population?

CLIC3 p.Val19Met (c.55G>A) is ultra-rare (popmax 0.0429%, mid) (gnomAD).

What do computational predictors say about CLIC3 p.Val19Met (c.55G>A)?

AlphaMissense predicts likely benign (score 0.2789) — an in-silico prediction, not a clinical call.

CLIC3 p.Val19Met

c.55G>A · rs764183952 · VCV2399771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0429%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2789	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.43	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 0.33	GERP -3.7, phastCons 0.02
Regional constraint	o/e 1.07	unconstrained · MANE · 1,859 bp · p 0.23 · regional, not allelic
Overall
CADD	18.57	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 0.0429% Middle Eastern · 2/4,662 alleles

Filtering AF 0.00753% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00189% 30/1,586,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0429%	2,331
African / African-American	0.00536%	18,671
Remaining individualsnot grpmax-eligible	0.00326%	30,678
European (non-Finnish)	0.0018%	55,601
South Asian	0.00114%	87,614

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.Val19Met
Coding: c.55G>A
MANE Select: NM_004669
dbSNP: rs764183952
Type: single nucleotide variant
Location: chr9:136995736 (GRCh38)
Gene constraint: LOEUF 1.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 2 PDB
Residue 19: a β-strand; the gst n-terminal domain; 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.Val19Glu Uncertain significance ★ ⚠ same residue
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.Arg191Cys Uncertain significance ★ ⚠ same type
CLIC3 p.Arg200His Uncertain significance ★ ⚠ same type
CLIC3 p.Arg204Ser 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-val19met (accessed [today's date]).

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