Is CC2D2A p.Glu775Lys (c.2323G>A) pathogenic?

CC2D2A p.Glu775Lys (c.2323G>A) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.621); Ultra-rare (popmax 0.0505%, mid); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Glu775Lys (c.2323G>A)?

CC2D2A p.Glu775Lys (c.2323G>A) is associated with Meckel syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Glu775Lys (c.2323G>A) in the general population?

CC2D2A p.Glu775Lys (c.2323G>A) is ultra-rare (popmax 0.0505%, mid) (gnomAD).

What do computational predictors say about CC2D2A p.Glu775Lys (c.2323G>A)?

AlphaMissense predicts likely pathogenic (score 0.621) — an in-silico prediction, not a clinical call.

CC2D2A p.Glu775Lys

c.2323G>A · rs751808973 · VCV634449

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.621	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -4.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0505% Middle Eastern · 3/5,936 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00733%

Overall 0.0062% 99/1,596,070 alleles · ultra-rare exomes 95/1,443,844 · genomes 4/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0505%	1,979
European (non-Finnish)	0.00763%	13,103
Admixed American	0.00502%	19,925
South Asian	0.00223%	44,795
Remaining individualsnot grpmax-eligible	0.00163%	61,510
African / African-American	0.00134%	74,816

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.Glu775Lys
Coding: c.2323G>A
MANE Select: NM_001378615
dbSNP: rs751808973
Type: single nucleotide variant
Location: chr4:15550965 (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

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

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

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-glu775lys (accessed [today's date]).

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