Is CACNA2D4 p.Asp729= (c.2187C>T) pathogenic?

CACNA2D4 p.Asp729= (c.2187C>T) is classified Benign in CACNA2D4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Low-frequency (popmax 4.15%, sas); Associated with retinal cone dystrophy 4.

What condition is associated with CACNA2D4 p.Asp729= (c.2187C>T)?

CACNA2D4 p.Asp729= (c.2187C>T) is associated with retinal cone dystrophy 4 (ClinVar).

How common is CACNA2D4 p.Asp729= (c.2187C>T) in the general population?

CACNA2D4 p.Asp729= (c.2187C>T) is low-frequency (popmax 4.15%, 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.Asp729=

c.2187C>T · rs78335326 · VCV166782

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.15%, 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 -8.7	GERP -4.2
Overall
CADD	0.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.15% South Asian · 3,767/90,856 alleles

Filtering AF 4.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.99%

Overall 0.446% 7,199/1,612,834 alleles · low-frequency exomes 6,505/1,460,594 · genomes 694/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	4.15%	24
East Asian	1.3%	77
Remaining individualsnot grpmax-eligible	0.578%	173
Middle Eastern	0.578%	173
African / African-American	0.521%	192
Finnishnot grpmax-eligible	0.272%	368
European (non-Finnish)	0.153%	653
Admixed American	0.125%	799
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,907

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.Asp729=
Coding: c.2187C>T
MANE Select: NM_172364
dbSNP: rs78335326
Type: single nucleotide variant
Location: chr12:1854010 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.69

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.Asp729His 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
CACNA2D4 p.Arg724Trp Uncertain significance ★★ ⚠ same condition
CACNA2D4 p.Arg763Trp 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-asp729 (accessed [today's date]).

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