Is CCDC66 p.Pro451Ala (c.1351C>G) pathogenic?

CCDC66 p.Pro451Ala (c.1351C>G) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: ambiguous (0.5322); Very rare (popmax 0.00983%, nfe).

How common is CCDC66 p.Pro451Ala (c.1351C>G) in the general population?

CCDC66 p.Pro451Ala (c.1351C>G) is very rare (popmax 0.00983%, nfe) (gnomAD).

What do computational predictors say about CCDC66 p.Pro451Ala (c.1351C>G)?

AlphaMissense predicts ambiguous (score 0.5322) — an in-silico prediction, not a clinical call.

CCDC66 p.Pro451Ala

c.1351C>G · rs375034029 · VCV3139274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00983%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5322	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -9.63	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	24.7	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 0.00983% European (non-Finnish) · 116/1,180,036 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00776%

Overall 0.00768% 124/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00983%	10,173
Admixed American	0.00833%	11,998
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00134%	74,878

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: CCDC66
Protein: p.Pro451Ala
Coding: c.1351C>G
MANE Select: NM_001141947
dbSNP: rs375034029
Type: single nucleotide variant
Location: chr3:56593975 (GRCh38)
Gene constraint: LOEUF 1.135 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56

Full CCDC66 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC66 p.Ala114Val Uncertain significance ★ ⚠ same type
CCDC66 p.Ala142Gly Uncertain significance ★ ⚠ same type
CCDC66 p.Ala323Thr Uncertain significance ★ ⚠ same type
CCDC66 p.Ala668Pro Uncertain significance ★ ⚠ same type
CCDC66 p.Ala937Val Uncertain significance ★ ⚠ same type
CCDC66 p.Arg122Ser Uncertain significance ★ ⚠ same type
CCDC66 p.Arg443Cys Uncertain significance ★ same type
CCDC66 p.Arg443His Uncertain significance ★ same type

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/ccdc66-p-pro451ala (accessed [today's date]).

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