Is CCDC3 p.Arg226Ser (c.678G>T) pathogenic?

CCDC3 p.Arg226Ser (c.678G>T) is classified Uncertain significance in CCDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely pathogenic (0.6879); Very rare (popmax 0.00415%, nfe).

How common is CCDC3 p.Arg226Ser (c.678G>T) in the general population?

CCDC3 p.Arg226Ser (c.678G>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about CCDC3 p.Arg226Ser (c.678G>T)?

AlphaMissense predicts likely pathogenic (score 0.6879) — an in-silico prediction, not a clinical call.

CCDC3 p.Arg226Ser

c.678G>T · VCV3264183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6879	likely pathogenic
REVEL	0.131	moderately benign-leaning
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -2.1, phastCons 0.061
Regional constraint	o/e 1.18	unconstrained · MANE · 103 kb · p 0.00074 · regional, not allelic
Overall
CADD	22.1	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 0.00415% European (non-Finnish) · 49/1,180,034 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00342% 50/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: CCDC3
Protein: p.Arg226Ser
Coding: c.678G>T
MANE Select: NM_031455
Type: single nucleotide variant
Location: chr10:12898551 (GRCh38)
Gene constraint: LOEUF 1.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13

Full CCDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC3 p.Ala19Val Uncertain significance ★ ⚠ same type
CCDC3 p.Ala21Ser Uncertain significance ★ ⚠ same type
CCDC3 p.Ala21Thr Uncertain significance ★ ⚠ same type
CCDC3 p.Ala250Val Uncertain significance ★ ⚠ same type
CCDC3 p.Ala253Thr Uncertain significance ★ ⚠ same type
CCDC3 p.Arg20Cys Uncertain significance ★ ⚠ same type
CCDC3 p.Arg213Cys Uncertain significance ★ ⚠ same type
CCDC3 p.Arg215Trp 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/ccdc3-p-arg226ser (accessed [today's date]).

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