Is CC2D2A p.Arg699Leu (c.2096G>T) pathogenic?

CC2D2A p.Arg699Leu (c.2096G>T) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely benign (0.1937); Absent from gnomAD v4.1; Associated with Meckel syndrome, type 6.

What condition is associated with CC2D2A p.Arg699Leu (c.2096G>T)?

CC2D2A p.Arg699Leu (c.2096G>T) is associated with Meckel syndrome, type 6, Joubert syndrome 9, retinitis pigmentosa 93 (ClinVar).

How common is CC2D2A p.Arg699Leu (c.2096G>T) in the general population?

CC2D2A p.Arg699Leu (c.2096G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CC2D2A p.Arg699Leu (c.2096G>T)?

AlphaMissense predicts likely benign (score 0.1937) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg699Leu

c.2096G>T · VCV3590299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meckel syndrome, type 6

Computational evidence

Protein change
AlphaMissense	0.1937	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CC2D2A
Protein: p.Arg699Leu
Coding: c.2096G>T
MANE Select: NM_001378615
Type: single nucleotide variant
Location: chr4:15540929 (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

Meckel syndrome, type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 9 retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Arg699Gln Uncertain significance ★★ ⚠ same residue
CC2D2A p.Arg699Trp 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.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.2004-17A>G Pathogenic/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-arg699leu (accessed [today's date]).

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