Is CACNA2D4 p.Pro413= (c.1239G>A) pathogenic?

CACNA2D4 p.Pro413= (c.1239G>A) is classified Conflicting classifications of pathogenicity in CACNA2D4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-14). Rare (popmax 0.339%, sas); Associated with retinal cone dystrophy 4.

What condition is associated with CACNA2D4 p.Pro413= (c.1239G>A)?

CACNA2D4 p.Pro413= (c.1239G>A) is associated with retinal cone dystrophy 4 (ClinVar).

How common is CACNA2D4 p.Pro413= (c.1239G>A) in the general population?

CACNA2D4 p.Pro413= (c.1239G>A) is rare (popmax 0.339%, sas) (gnomAD).

How is Progressive cone dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CACNA2D4 p.Pro413=

c.1239G>A · rs201783863 · VCV288899

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.339%, sas)

Conditions

retinal cone dystrophy 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -4.2
Overall
CADD	0.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.339% South Asian · 309/91,038 alleles

Filtering AF 0.308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0389% 628/1,613,636 alleles · rare exomes 560/1,461,400 · genomes 68/152,236 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.339%	295
Admixed American	0.145%	690
Middle Eastern	0.116%	866
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
Remaining individualsnot grpmax-eligible	0.0608%	1,644
East Asian	0.0401%	2,492
European (non-Finnish)	0.0122%	8,193
African / African-American	0.00667%	15,001

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: CACNA2D4
Protein: p.Pro413=
Coding: c.1239G>A
MANE Select: NM_172364
dbSNP: rs201783863
Type: single nucleotide variant
Location: chr12:1884801 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.69
Residue 413: the vwfa domain

Full CACNA2D4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinal cone dystrophy 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive cone dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

CACNA2D4 p.Pro413Leu Uncertain significance ★★ ⚠ same residue
CACNA2D4 p.Pro413Arg Uncertain significance ★ ⚠ same residue
CACNA2D4 p.Pro413Gln Uncertain significance ★ ⚠ same residue
CACNA2D4 c.2552-3T>C Uncertain significance ★★ same condition
CACNA2D4 p.Ala407Thr Uncertain significance ★★ ⚠ same condition
CACNA2D4 p.Ala555Thr Uncertain significance ★★ ⚠ same condition
CACNA2D4 p.Arg135Trp Uncertain significance ★★ ⚠ same condition
CACNA2D4 p.Arg571Trp Uncertain significance ★★ ⚠ same condition

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/cacna2d4-p-pro413 (accessed [today's date]).

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