Is CC2D2A p.Arg324His (c.971G>A) pathogenic?

CC2D2A p.Arg324His (c.971G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0874); Ultra-rare (popmax 0.0135%, afr); Associated with COACH syndrome 2.

What condition is associated with CC2D2A p.Arg324His (c.971G>A)?

CC2D2A p.Arg324His (c.971G>A) is associated with COACH syndrome 2, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Arg324His (c.971G>A) in the general population?

CC2D2A p.Arg324His (c.971G>A) is ultra-rare (popmax 0.0135%, afr) (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.Arg324His (c.971G>A)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg324His

c.971G>A · rs113371687 · VCV285506

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COACH syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.79	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 0.53	GERP -4.2
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	17.29	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 0.0135% African / African-American · 10/74,310 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00554%

Overall 0.00196% 31/1,581,222 alleles · ultra-rare exomes 28/1,429,028 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0135%	7,431
East Asian	0.00695%	14,387
Remaining individualsnot grpmax-eligible	0.00489%	20,431
Admixed American	0.00181%	55,398
South Asian	0.00116%	85,904
European (non-Finnish)	0.00112%	89,479

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.Arg324His
Coding: c.971G>A
MANE Select: NM_001378615
dbSNP: rs113371687
Type: single nucleotide variant
Location: chr4:15515958 (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

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.Arg324Cys Uncertain significance ★★ ⚠ 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
CC2D2A c.1466+2T>C 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-arg324his (accessed [today's date]).

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