Is CACNG4 p.Ile26Val (c.76A>G) pathogenic?

CACNG4 p.Ile26Val (c.76A>G) is classified Uncertain significance in CACNG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.0653); Very rare (popmax 0.000424%, nfe).

How common is CACNG4 p.Ile26Val (c.76A>G) in the general population?

CACNG4 p.Ile26Val (c.76A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CACNG4 p.Ile26Val (c.76A>G)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

CACNG4 p.Ile26Val

c.76A>G · VCV4218051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -6.81	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 7.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 60 kb · p 0.00018 · regional, not allelic
Overall
CADD	21.5	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 0.000424% European (non-Finnish) · 5/1,178,614 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,459,694 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: CACNG4
Protein: p.Ile26Val
Coding: c.76A>G
MANE Select: NM_014405
Type: single nucleotide variant
Location: chr17:66964987 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 65.80

Full CACNG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNG4 p.Ala195Thr Uncertain significance ★ ⚠ same type
CACNG4 p.Ala224Val Uncertain significance ★ ⚠ same type
CACNG4 p.Ala268Asp Uncertain significance ★ ⚠ same type
CACNG4 p.Arg133His Uncertain significance ★ ⚠ same type
CACNG4 p.Arg219Trp Uncertain significance ★ ⚠ same type
CACNG4 p.Arg322Gln Uncertain significance ★ ⚠ same type
CACNG4 p.Arg323Gln Uncertain significance ★ ⚠ same type
CACNG4 p.Arg3Gln 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/cacng4-p-ile26val (accessed [today's date]).

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