Is CLIC6 p.Val226Leu (c.676G>C) pathogenic?

CLIC6 p.Val226Leu (c.676G>C) is classified Uncertain significance in CLIC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1277); Very rare (popmax 9.27e-05%, nfe).

How common is CLIC6 p.Val226Leu (c.676G>C) in the general population?

CLIC6 p.Val226Leu (c.676G>C) is very rare (popmax 9.27e-05%, nfe) (gnomAD).

What do computational predictors say about CLIC6 p.Val226Leu (c.676G>C)?

AlphaMissense predicts likely benign (score 0.1277) — an in-silico prediction, not a clinical call.

CLIC6 p.Val226Leu

c.676G>C · VCV4229879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1277 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.27e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1277	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -4.86	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 -3.9	GERP -0.17
Regional constraint	o/e 0.48	unconstrained · MANE · 206 bp · p 2.3e-08 · regional, not allelic
Overall
CADD	8.846	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 9.27e-05% European (non-Finnish) · 1/1,078,726 alleles

Overall 8.09e-05% 1/1,235,478 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: CLIC6
Protein: p.Val226Leu
Coding: c.676G>C
MANE Select: NM_053277
Type: single nucleotide variant
Location: chr21:34670064 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.24
Residue 226: the 'disordered' region; the '13 x 10 aa tandem repeat of g-d-[sng]-[vim]-[deq]-a-[eag]-[gdve]-[prg]-[lavp]' region

Full CLIC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC6 p.Arg436Pro Benign ★★ same type
CLIC6 p.Arg640Lys Benign ★★ same type
CLIC6 p.Asp616= Benign ★★ same type
CLIC6 p.Glu401= Likely benign ★★ same type
CLIC6 p.Ile651Val Benign ★★ same type
CLIC6 p.Ser550= Benign ★★ same type
CLIC6 p.Thr667= Benign ★★ same type
CLIC6 p.Val180Leu Benign ★★ ⚠ 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/clic6-p-val226leu (accessed [today's date]).

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