Is CLIC2 p.Arg145His (c.434G>A) pathogenic?

CLIC2 p.Arg145His (c.434G>A) is classified Likely benign in CLIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-25). AlphaMissense: likely benign (0.1295); Ultra-rare (popmax 0.023%, mid); Associated with X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome.

How common is CLIC2 p.Arg145His (c.434G>A) in the general population?

CLIC2 p.Arg145His (c.434G>A) is ultra-rare (popmax 0.023%, mid) (gnomAD).

What do computational predictors say about CLIC2 p.Arg145His (c.434G>A)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

CLIC2 p.Arg145His

Q: What condition is associated with CLIC2 p.Arg145His (c.434G>A)?

CLIC2 p.Arg145His (c.434G>A) is associated with X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome (ClinVar).

Q: How is X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.434G>A · rs782037891 · VCV1321269

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.696	pathogenic-leaning
SaProt	LLR -9.60	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 0.071, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 57 kb · p 0.013 · regional, not allelic
Overall
CADD	21.3	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 0.023% Middle Eastern · 1/4,340 alleles

Filtering AF 0.0094% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00704% 85/1,208,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,340
African / African-American	0.0175%	5,722
South Asian	0.0141%	7,096
East Asian	0.0119%	8,438
Remaining individualsnot grpmax-eligible	0.0105%	9,510
European (non-Finnish)	0.00627%	15,952
Admixed American	0.00218%	45,775

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.Arg145His
Coding: c.434G>A
MANE Select: NM_001289
dbSNP: rs782037891
Type: single nucleotide variant
Location: chrX:155279297 (GRCh38)
Structure: AlphaFold pLDDT 93.28 · 3 PDB
Residue 145: the gst c-terminal domain; an α-helix; the 'c-terminal' region

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

Disease context

X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CLIC2 p.Arg35Cys Uncertain significance ★ ⚠ same condition
CLIC2 p.Gly7Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
CLIC2 p.His101Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
CLIC2 p.Lys57Asn Uncertain significance ★ ⚠ same condition
CLIC2 p.Ala131Glu Uncertain significance ⚠ same condition
CLIC2 c.57+10C>T Benign/Likely benign ★★ same type
CLIC2 c.*19= Benign ★★ same type
CLIC2 p.Pro160Ala Benign/Likely 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/clic2-p-arg145his (accessed [today's date]).

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