Is CC2D2A p.Arg103Cys (c.307C>T) pathogenic?

CC2D2A p.Arg103Cys (c.307C>T) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: ambiguous (0.5095); Ultra-rare (popmax 0.033%, mid); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Arg103Cys (c.307C>T)?

CC2D2A p.Arg103Cys (c.307C>T) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg103Cys (c.307C>T) in the general population?

CC2D2A p.Arg103Cys (c.307C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CC2D2A p.Arg103Cys (c.307C>T)?

AlphaMissense predicts ambiguous (score 0.5095) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg103Cys

c.307C>T · rs367699902 · VCV1500749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.5095	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	33.0	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 0.033% Middle Eastern · 2/6,064 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000995% 16/1,607,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,032
Admixed American	0.00169%	59,142
Remaining individualsnot grpmax-eligible	0.00161%	62,294
European (non-Finnish)	0.00102%	98,195

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.Arg103Cys
Coding: c.307C>T
MANE Select: NM_001378615
dbSNP: rs367699902
Type: single nucleotide variant
Location: chr4:15502488 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 103: the 'disordered' region

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: Joubert syndrome

Similar variants

CC2D2A p.Arg103His Uncertain significance ★★ ⚠ same residue
CC2D2A p.Arg103fs Pathogenic ★ 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-arg103cys (accessed [today's date]).

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