Is CLIC5 p.Arg247Leu (c.740G>T) pathogenic?

CLIC5 p.Arg247Leu (c.740G>T) is classified Uncertain significance in CLIC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely pathogenic (0.7733); Ultra-rare (popmax 0.0156%, eas).

How common is CLIC5 p.Arg247Leu (c.740G>T) in the general population?

CLIC5 p.Arg247Leu (c.740G>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CLIC5 p.Arg247Leu (c.740G>T)?

AlphaMissense predicts likely pathogenic (score 0.7733) — an in-silico prediction, not a clinical call.

CLIC5 p.Arg247Leu

c.740G>T · VCV3493657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7733	likely pathogenic
REVEL	0.737	pathogenic-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 112 kb · p 0.41 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R406L vs ClinVar R247L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,878 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000558% 9/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,411
Admixed American	0.00333%	30,003

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.Arg247Leu
Coding: c.740G>T
MANE Select: NM_016929
Type: single nucleotide variant
Location: chr6:45903104 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 3 PDB
Residue 247: an α-helix

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

Similar variants

CLIC5 p.Arg247Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg247leu (accessed [today's date]).

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