Is CC2D2A p.Val1045= (c.3135G>A) pathogenic?

CC2D2A p.Val1045= (c.3135G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.027%, nfe); Associated with retinitis pigmentosa 93.

What condition is associated with CC2D2A p.Val1045= (c.3135G>A)?

CC2D2A p.Val1045= (c.3135G>A) is associated with retinitis pigmentosa 93, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Val1045= (c.3135G>A) in the general population?

CC2D2A p.Val1045= (c.3135G>A) is ultra-rare (popmax 0.027%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

CC2D2A p.Val1045=

c.3135G>A · rs371608031 · VCV388321

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, nfe)

Conditions

retinitis pigmentosa 93

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 3.9	GERP 0.91, phastCons 1
Overall
CADD	9.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.027% European (non-Finnish) · 318/1,179,334 alleles

Filtering AF 0.0245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.0214% 345/1,612,340 alleles · ultra-rare exomes 320/1,460,124 · genomes 25/152,216 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,672
European (non-Finnish)grpmax	0.027%	3,709
Finnishnot grpmax-eligible	0.00782%	12,783
African / African-American	0.00401%	24,967
Admixed American	0.00334%	29,917

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CC2D2A
Protein: p.Val1045=
Coding: c.3135G>A
MANE Select: NM_001378615
dbSNP: rs371608031
Type: single nucleotide variant
Location: chr4:15563475 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 1045: the c2 domain; a UniProt-annotated variant site (in jbts9)

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa 93 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome Meckel syndrome COACH syndrome 2 COACH syndrome 1

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CC2D2A p.Val1045Ala Pathogenic/Likely pathogenic ★★ same residue
CC2D2A p.Val1045Met Uncertain significance ★ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1149+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.123+2T>G Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>C Likely pathogenic ★★ same condition
CC2D2A c.1466+1G>A Likely pathogenic ★★ 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/cc2d2a-p-val1045 (accessed [today's date]).

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