Is CLIC4 p.Phe80Leu (c.240C>A) pathogenic?

CLIC4 p.Phe80Leu (c.240C>A) is classified Uncertain significance in CLIC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.9911); Very rare (popmax 0.00934%, afr).

How common is CLIC4 p.Phe80Leu (c.240C>A) in the general population?

CLIC4 p.Phe80Leu (c.240C>A) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CLIC4 p.Phe80Leu (c.240C>A)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

CLIC4 p.Phe80Leu

c.240C>A · rs377164280 · VCV3145763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic
REVEL	0.175	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,908 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00149% 24/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,701
European (non-Finnish)	0.00144%	69,412

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: CLIC4
Protein: p.Phe80Leu
Coding: c.240C>A
MANE Select: NM_013943
dbSNP: rs377164280
Type: single nucleotide variant
Location: chr1:24814151 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 3 PDB
Residue 80: a β-strand; the 'required for insertion into the membrane' region

Full CLIC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC4 p.Arg133Ser Uncertain significance ★ ⚠ same type
CLIC4 p.Arg206His Uncertain significance ★ ⚠ same type
CLIC4 p.Asn115Thr Uncertain significance ★ ⚠ same type
CLIC4 p.Asp209Asn Uncertain significance ★ ⚠ same type
CLIC4 p.Asp228Asn Uncertain significance ★ same type
CLIC4 p.Glu183Gly Uncertain significance ★ ⚠ same type
CLIC4 p.Glu241Gly Uncertain significance ★ ⚠ same type
CLIC4 p.Gly181Ser 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/clic4-p-phe80leu (accessed [today's date]).

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