Is CC2D2A p.Arg680His (c.2039G>A) pathogenic?

CC2D2A p.Arg680His (c.2039G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0931); Ultra-rare (popmax 0.0413%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CC2D2A p.Arg680His (c.2039G>A)?

CC2D2A p.Arg680His (c.2039G>A) is associated with Inborn genetic diseases, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Arg680His (c.2039G>A) in the general population?

CC2D2A p.Arg680His (c.2039G>A) is ultra-rare (popmax 0.0413%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Arg680His (c.2039G>A)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg680His

c.2039G>A · rs200236654 · VCV194820

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.66	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 9.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	21.6	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 0.0413% European (non-Finnish) · 484/1,173,072 alleles

Filtering AF 0.0382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.037%

Overall 0.0327% 523/1,599,732 alleles · ultra-rare exomes 493/1,447,570 · genomes 30/152,162 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0413%	2,424
Remaining individualsnot grpmax-eligible	0.0226%	4,429
African / African-American	0.0201%	4,977
South Asian	0.0091%	10,991
East Asian	0.00225%	44,396
Admixed American	0.00172%	58,188

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.Arg680His
Coding: c.2039G>A
MANE Select: NM_001378615
dbSNP: rs200236654
Type: single nucleotide variant
Location: chr4:15540872 (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: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome Meckel syndrome inherited retinal dystrophy COACH syndrome 1

Similar variants

CC2D2A p.Arg680Cys Uncertain significance ★ ⚠ same residue
CC2D2A p.Arg680= Likely benign ★ 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-arg680his (accessed [today's date]).

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