Is CC2D2A p.Val686Met (c.2056G>A) pathogenic?

CC2D2A p.Val686Met (c.2056G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-14). AlphaMissense: ambiguous (0.3485); Ultra-rare (popmax 0.0242%, nfe); Associated with Joubert syndrome 9.

What condition is associated with CC2D2A p.Val686Met (c.2056G>A)?

CC2D2A p.Val686Met (c.2056G>A) is associated with Joubert syndrome 9, Meckel syndrome, type 6, Joubert syndrome (ClinVar).

How common is CC2D2A p.Val686Met (c.2056G>A) in the general population?

CC2D2A p.Val686Met (c.2056G>A) is ultra-rare (popmax 0.0242%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Val686Met (c.2056G>A)?

AlphaMissense predicts ambiguous (score 0.3485) — an in-silico prediction, not a clinical call.

CC2D2A p.Val686Met

c.2056G>A · rs369476930 · VCV347764

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3485 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Joubert syndrome 9

Computational evidence

Protein change
AlphaMissense	0.3485	ambiguous
REVEL	0.21	benign-leaning
SaProt	LLR -9.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.39, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	23.2	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 0.0242% European (non-Finnish) · 283/1,170,770 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0231% 368/1,595,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0763%	1,311
Ashkenazi Jewishnot grpmax-eligible	0.0444%	2,250
Remaining individualsnot grpmax-eligible	0.0307%	3,258
European (non-Finnish)grpmax	0.0242%	4,137
Admixed American	0.00348%	28,766
South Asian	0.00229%	43,684
African / African-American	0.00134%	74,576

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val686Met
Coding: c.2056G>A
MANE Select: NM_001378615
dbSNP: rs369476930
Type: single nucleotide variant
Location: chr4:15540889 (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

Joubert syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Val686= 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
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-val686met (accessed [today's date]).

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