Is CLIC4 p.Val98Ala (c.293T>C) pathogenic?

CLIC4 p.Val98Ala (c.293T>C) is classified Uncertain significance in CLIC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-06). AlphaMissense: likely benign (0.2155); Very rare (popmax 0.00167%, amr).

How common is CLIC4 p.Val98Ala (c.293T>C) in the general population?

CLIC4 p.Val98Ala (c.293T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLIC4 p.Val98Ala (c.293T>C)?

AlphaMissense predicts likely benign (score 0.2155) — an in-silico prediction, not a clinical call.

CLIC4 p.Val98Ala

c.293T>C · VCV3493653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2155	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.88, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,788 alleles

Overall 6.84e-05% 1/1,460,996 alleles · very rare

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.Val98Ala
Coding: c.293T>C
MANE Select: NM_013943
Type: single nucleotide variant
Location: chr1:24814204 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 3 PDB
Residue 98: an α-helix; the gst c-terminal domain; 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-val98ala (accessed [today's date]).

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