Is CC2D2A p.Val1583Ile (c.4747G>A) pathogenic?

CC2D2A p.Val1583Ile (c.4747G>A) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0934); Ultra-rare (popmax 0.0661%, sas); Associated with Inborn genetic diseases.

What condition is associated with CC2D2A p.Val1583Ile (c.4747G>A)?

CC2D2A p.Val1583Ile (c.4747G>A) is associated with Inborn genetic diseases, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Val1583Ile (c.4747G>A) in the general population?

CC2D2A p.Val1583Ile (c.4747G>A) is ultra-rare (popmax 0.0661%, sas) (gnomAD).

What do computational predictors say about CC2D2A p.Val1583Ile (c.4747G>A)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

CC2D2A p.Val1583Ile

c.4747G>A · rs371196379 · VCV935368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -4.68	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.69 · regional, not allelic
Overall
CADD	24.2	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 0.0661% South Asian · 60/90,794 alleles

Filtering AF 0.0527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00496% 80/1,611,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0661%	1,513
Middle Eastern	0.0165%	6,054
Admixed American	0.015%	6,655
Remaining individualsnot grpmax-eligible	0.00801%	12,477
European (non-Finnish)	0.000424%	235,733

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.Val1583Ile
Coding: c.4747G>A
MANE Select: NM_001378615
dbSNP: rs371196379
Type: single nucleotide variant
Location: chr4:15601309 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Val1583= Likely benign ★ same residue
CC2D2A p.Val1583fs Uncertain significance ★★ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.123+2T>G Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>C Likely pathogenic ★★ same condition
CC2D2A c.1466+1G>A Likely pathogenic ★★ same condition
CC2D2A c.1466+2T>C Likely pathogenic ★★ same condition
CC2D2A c.1608-2A>G 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-val1583ile (accessed [today's date]).

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