Is CCDC66 p.Lys120Arg (c.359A>G) pathogenic?

CCDC66 p.Lys120Arg (c.359A>G) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: likely benign (0.0889); Rare (popmax 0.149%, mid).

How common is CCDC66 p.Lys120Arg (c.359A>G) in the general population?

CCDC66 p.Lys120Arg (c.359A>G) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about CCDC66 p.Lys120Arg (c.359A>G)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

CCDC66 p.Lys120Arg

c.359A>G · VCV3828715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -7.43	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 5.2	GERP 0.77, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	19.86	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 0.149% Middle Eastern · 9/6,058 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00434% 70/1,613,958 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
Admixed American	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.0064%	15,624
European (non-Finnish)	0.00331%	30,253
South Asian	0.0022%	45,540
African / African-American	0.00133%	75,066

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.Lys120Arg
Coding: c.359A>G
MANE Select: NM_001141947
Type: single nucleotide variant
Location: chr3:56563940 (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-lys120arg (accessed [today's date]).

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