Is CLIC5 p.Arg250Gln (c.749G>A) pathogenic?

CLIC5 p.Arg250Gln (c.749G>A) is classified Uncertain significance in CLIC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.1116); Ultra-rare (popmax 0.0401%, eas).

How common is CLIC5 p.Arg250Gln (c.749G>A) in the general population?

CLIC5 p.Arg250Gln (c.749G>A) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about CLIC5 p.Arg250Gln (c.749G>A)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

CLIC5 p.Arg250Gln

c.749G>A · VCV4692888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.27	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 2.5	GERP 1.2, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 112 kb · p 0.41 · regional, not allelic
Overall
CADD	19.83	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R409Q vs ClinVar R250Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% East Asian · 18/44,862 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00229% 37/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,492
South Asian	0.00439%	22,770
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.00102%	98,333

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: CLIC5
Protein: p.Arg250Gln
Coding: c.749G>A
MANE Select: NM_016929
Type: single nucleotide variant
Location: chr6:45903095 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 3 PDB
Residue 250: an α-helix

Full CLIC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC5 p.Arg250Ter Uncertain significance ★ same residue
CLIC5 p.Arg203His Uncertain significance ★★ ⚠ same type
CLIC5 p.Arg216Gln Uncertain significance ★★ ⚠ same type
CLIC5 p.Arg224His Uncertain significance ★★ ⚠ same type
CLIC5 p.Asn204Thr Uncertain significance ★★ ⚠ same type
CLIC5 p.His54Arg Uncertain significance ★★ ⚠ same type
CLIC5 p.Ile118Val Uncertain significance ★★ ⚠ same type
CLIC5 p.Ile41Phe 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/clic5-p-arg250gln (accessed [today's date]).

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