Is CC2D2A p.Arg912Ser (c.2736G>C) pathogenic?

CC2D2A p.Arg912Ser (c.2736G>C) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-01). AlphaMissense: likely pathogenic (0.6073); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CC2D2A p.Arg912Ser (c.2736G>C)?

CC2D2A p.Arg912Ser (c.2736G>C) is associated with Inborn genetic diseases, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Arg912Ser (c.2736G>C) in the general population?

CC2D2A p.Arg912Ser (c.2736G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CC2D2A p.Arg912Ser (c.2736G>C)?

AlphaMissense predicts likely pathogenic (score 0.6073) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg912Ser

c.2736G>C · rs1471618183 · VCV954459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6073	likely pathogenic
REVEL	0.288	benign-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.02, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	21.7	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 0.00223% East Asian · 1/44,844 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,228 alleles · very rare exomes 1/1,461,130 · genomes 3/152,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,844
European (non-Finnish)	0.000254%	393,187

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.Arg912Ser
Coding: c.2736G>C
MANE Select: NM_001378615
dbSNP: rs1471618183
Type: single nucleotide variant
Location: chr4:15557414 (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.Arg912Gly 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
CC2D2A c.2004-17A>G Pathogenic/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-arg912ser (accessed [today's date]).

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