Is CC2D2A p.Arg495His (c.1484G>A) pathogenic?

CC2D2A p.Arg495His (c.1484G>A) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2858); Ultra-rare (popmax 0.0334%, mid); Associated with Meckel syndrome, type 6.

What condition is associated with CC2D2A p.Arg495His (c.1484G>A)?

CC2D2A p.Arg495His (c.1484G>A) is associated with Meckel syndrome, type 6, Joubert syndrome 9, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg495His (c.1484G>A) in the general population?

CC2D2A p.Arg495His (c.1484G>A) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about CC2D2A p.Arg495His (c.1484G>A)?

AlphaMissense predicts likely benign (score 0.2858) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg495His

c.1484G>A · rs373906628 · VCV420965

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Meckel syndrome, type 6

Computational evidence

Protein change
AlphaMissense	0.2858	likely benign
REVEL	0.551	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.0334% Middle Eastern · 2/5,982 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0094%

Overall 0.00538% 85/1,579,124 alleles · ultra-rare exomes 69/1,426,904 · genomes 16/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,991
East Asian	0.0229%	4,361
African / African-American	0.00824%	12,133
European (non-Finnish)	0.00513%	19,499
Remaining individualsnot grpmax-eligible	0.00491%	20,365
Admixed American	0.004%	25,000
South Asian	0.00243%	41,163

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.Arg495His
Coding: c.1484G>A
MANE Select: NM_001378615
dbSNP: rs373906628
Type: single nucleotide variant
Location: chr4:15533210 (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 Joubert syndrome Meckel syndrome retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Arg495Cys Uncertain significance ★ ⚠ same residue
CC2D2A p.Arg495= 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-arg495his (accessed [today's date]).

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