Is CC2D2A p.Val660Ile (c.1978G>A) pathogenic?

CC2D2A p.Val660Ile (c.1978G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0642); Low-frequency (popmax 2.27%, afr); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Val660Ile (c.1978G>A)?

CC2D2A p.Val660Ile (c.1978G>A) is associated with Meckel syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Val660Ile (c.1978G>A) in the general population?

CC2D2A p.Val660Ile (c.1978G>A) is low-frequency (popmax 2.27%, afr) (gnomAD).

What do computational predictors say about CC2D2A p.Val660Ile (c.1978G>A)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

CC2D2A p.Val660Ile

c.1978G>A · rs16892134 · VCV210608

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.27%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.57	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 1.7	GERP -4.8, phastCons 0.95
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	0.37	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 2.27% African / African-American · 1,699/74,688 alleles

Filtering AF 2.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.15%

Overall 0.122% 1,944/1,595,412 alleles · low-frequency exomes 1,030/1,443,192 · genomes 914/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.27%	44
Admixed American	0.141%	711
Remaining individualsnot grpmax-eligible	0.126%	792
Middle Eastern	0.0999%	1,001
European (non-Finnish)	0.00641%	15,602
South Asian	0.00568%	17,598

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.Val660Ile
Coding: c.1978G>A
MANE Select: NM_001378615
dbSNP: rs16892134
Type: single nucleotide variant
Location: chr4:15538112 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 660: a UniProt-annotated variant site (in)

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome

Similar variants

CC2D2A p.Val660Leu Conflicting classifications of pathogenicity ★ ⚠ 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-val660ile (accessed [today's date]).

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