Is CLIC5 p.Arg247Cys (c.739C>T) pathogenic?

CLIC5 p.Arg247Cys (c.739C>T) is classified Conflicting classifications of pathogenicity in CLIC5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-11-26). AlphaMissense: likely pathogenic (0.7053); Rare (popmax 0.152%, amr).

How common is CLIC5 p.Arg247Cys (c.739C>T) in the general population?

CLIC5 p.Arg247Cys (c.739C>T) is rare (popmax 0.152%, amr) (gnomAD).

What do computational predictors say about CLIC5 p.Arg247Cys (c.739C>T)?

AlphaMissense predicts likely pathogenic (score 0.7053) — an in-silico prediction, not a clinical call.

CLIC5 p.Arg247Cys

c.739C>T · rs202022202 · VCV667217

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7053 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.152%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7053	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -7.87	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 112 kb · p 0.41 · regional, not allelic
Overall
CADD	33.0	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 R406C vs ClinVar R247C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.152% Admixed American · 91/60,022 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.0112% 181/1,614,176 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.152%	660
East Asian	0.0512%	1,951
African / African-American	0.0147%	6,822
Remaining individualsnot grpmax-eligible	0.0144%	6,945
South Asian	0.00549%	18,216
European (non-Finnish)	0.00347%	28,781
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg247Cys
Coding: c.739C>T
MANE Select: NM_016929
dbSNP: rs202022202
Type: single nucleotide variant
Location: chr6:45903105 (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.Arg247Leu 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-arg247cys (accessed [today's date]).

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