Is CLIC1 p.Val12Met (c.34G>A) pathogenic?

CLIC1 p.Val12Met (c.34G>A) is classified Uncertain significance in CLIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.996); Very rare (popmax 0.00446%, eas).

How common is CLIC1 p.Val12Met (c.34G>A) in the general population?

CLIC1 p.Val12Met (c.34G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CLIC1 p.Val12Met (c.34G>A)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CLIC1 p.Val12Met

c.34G>A · rs748522729 · VCV2274875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic
REVEL	0.223	benign-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.48, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 5,455 bp · p 0.00014 · regional, not allelic
Overall
CADD	26.1	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 0.00446% East Asian · 2/44,830 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000548% 8/1,460,724 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,415
South Asian	0.0011%	91,072
European (non-Finnish)	0.000424%	235,980

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.Val12Met
Coding: c.34G>A
MANE Select: NM_001288
dbSNP: rs748522729
Type: single nucleotide variant
Location: chr6:31736267 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.34 · 18 PDB
Residue 12: a β-strand; the 'required for insertion into the membrane' region

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-val12met (accessed [today's date]).

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