Is CCDC66 p.Arg122Ser (c.366A>C) pathogenic?

CCDC66 p.Arg122Ser (c.366A>C) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1981); Ultra-rare (popmax 0.0132%, sas).

How common is CCDC66 p.Arg122Ser (c.366A>C) in the general population?

CCDC66 p.Arg122Ser (c.366A>C) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about CCDC66 p.Arg122Ser (c.366A>C)?

AlphaMissense predicts likely benign (score 0.1981) — an in-silico prediction, not a clinical call.

CCDC66 p.Arg122Ser

c.366A>C · VCV4221418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1981	likely benign
REVEL	0.38	indeterminate
SaProt	LLR -4.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP -0.41, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	16.41	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 0.0132% South Asian · 12/91,082 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000744% 12/1,613,866 alleles · ultra-rare

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.Arg122Ser
Coding: c.366A>C
MANE Select: NM_001141947
Type: single nucleotide variant
Location: chr3:56563947 (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.Arg443Cys Uncertain significance ★ ⚠ same type
CCDC66 p.Arg443His Uncertain significance ★ ⚠ same type
CCDC66 p.Arg479Cys 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-arg122ser (accessed [today's date]).

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