Is CC2D2A p.His259= (c.777C>T) pathogenic?

CC2D2A p.His259= (c.777C>T) is classified Benign in CC2D2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 31.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Joubert syndrome.

What condition is associated with CC2D2A p.His259= (c.777C>T)?

CC2D2A p.His259= (c.777C>T) is associated with Joubert syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

CC2D2A p.His259=

Q: How common is CC2D2A p.His259= (c.777C>T) in the general population?

CC2D2A p.His259= (c.777C>T) is common (popmax 31.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.777C>T · rs2286976 · VCV126248

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 31.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -5.3
Overall
CADD	0.076	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 31.8% East Asian · 14,278/44,836 alleles

Filtering AF 31.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.2%

Overall 3.63% 58,469/1,612,680 alleles · common exomes 51,521/1,460,492 · genomes 6,948/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	31.8%	3
Middle Eastern	8.65%	12
Remaining individualsnot grpmax-eligible	5.69%	18
Ashkenazi Jewishnot grpmax-eligible	5.33%	19
African / African-American	5.09%	20
Finnishnot grpmax-eligible	3.61%	28
European (non-Finnish)	2.47%	41
Admixed American	2.32%	43
South Asian	2.15%	47

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.His259=
Coding: c.777C>T
MANE Select: NM_001378615
dbSNP: rs2286976
Type: single nucleotide variant
Location: chr4:15514766 (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

Joubert syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Meckel syndrome

Similar variants

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
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-his259 (accessed [today's date]).

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