Is CLIC5 p.Pro72Leu (c.215C>T) pathogenic?

CLIC5 p.Pro72Leu (c.215C>T) is classified Uncertain significance in CLIC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-26). AlphaMissense: likely pathogenic (0.8941); Very rare (popmax 0.00669%, eas).

How common is CLIC5 p.Pro72Leu (c.215C>T) in the general population?

CLIC5 p.Pro72Leu (c.215C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CLIC5 p.Pro72Leu (c.215C>T)?

AlphaMissense predicts likely pathogenic (score 0.8941) — an in-silico prediction, not a clinical call.

CLIC5 p.Pro72Leu

c.215C>T · rs147816908 · VCV1382493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8941	likely pathogenic
REVEL	0.357	indeterminate
SaProt	LLR -11.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 112 kb · p 0.41 · regional, not allelic
Overall
CADD	29.0	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 P231L vs ClinVar P72L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00167% 27/1,613,968 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
South Asian	0.00439%	22,765
European (non-Finnish)	0.00161%	62,100
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Pro72Leu
Coding: c.215C>T
MANE Select: NM_016929
dbSNP: rs147816908
Type: single nucleotide variant
Location: chr6:45949340 (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.Pro72= Likely benign ★★ 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-pro72leu (accessed [today's date]).

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