Is CLIC5 p.Phe227Cys (c.680T>G) pathogenic?

CLIC5 p.Phe227Cys (c.680T>G) is classified Uncertain significance in CLIC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.00666%, amr).

How common is CLIC5 p.Phe227Cys (c.680T>G) in the general population?

CLIC5 p.Phe227Cys (c.680T>G) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about CLIC5 p.Phe227Cys (c.680T>G)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

CLIC5 p.Phe227Cys

c.680T>G · VCV4755160

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 4% in CLIC5
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -14.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 112 kb · p 0.41 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 F386C vs ClinVar F227C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000342% 5/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
East Asian	0.00223%	44,882

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.Phe227Cys
Coding: c.680T>G
MANE Select: NM_016929
Type: single nucleotide variant
Location: chr6:45903164 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 3 PDB

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

Similar variants

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
CLIC5 p.Leu96Phe 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-phe227cys (accessed [today's date]).

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