Is CC2D2A p.Arg103His (c.308G>A) pathogenic?

CC2D2A p.Arg103His (c.308G>A) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-05). AlphaMissense: likely benign (0.2511); Ultra-rare (popmax 0.0186%, amr); Associated with COACH syndrome 2.

What condition is associated with CC2D2A p.Arg103His (c.308G>A)?

CC2D2A p.Arg103His (c.308G>A) is associated with COACH syndrome 2, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Arg103His (c.308G>A) in the general population?

CC2D2A p.Arg103His (c.308G>A) is ultra-rare (popmax 0.0186%, amr) (gnomAD).

How is Joubert syndrome with hepatic defect inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CC2D2A p.Arg103His (c.308G>A)?

AlphaMissense predicts likely benign (score 0.2511) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg103His

c.308G>A · rs566281691 · VCV1438122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COACH syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2511	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -8.18	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 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	25.7	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 0.0186% Admixed American · 11/59,096 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00806%

Overall 0.00193% 31/1,607,690 alleles · ultra-rare exomes 22/1,455,994 · genomes 9/151,696 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0186%	5,372
East Asian	0.0112%	8,957
South Asian	0.00565%	17,708
Remaining individualsnot grpmax-eligible	0.00321%	31,140
European (non-Finnish)	0.000679%	147,276

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.Arg103His
Coding: c.308G>A
MANE Select: NM_001378615
dbSNP: rs566281691
Type: single nucleotide variant
Location: chr4:15502489 (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

COACH syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome Meckel syndrome retinitis pigmentosa 93

For Joubert syndrome with hepatic defect (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

CC2D2A p.Arg103Cys Uncertain significance ★ ⚠ same residue
CC2D2A p.Arg103fs Pathogenic ★ same residue
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

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-arg103his (accessed [today's date]).

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