Is CCDC3 p.Pro25Leu (c.74C>T) pathogenic?

CCDC3 p.Pro25Leu (c.74C>T) is classified Uncertain significance in CCDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.8125); Very rare (popmax 0.00154%, afr).

How common is CCDC3 p.Pro25Leu (c.74C>T) in the general population?

CCDC3 p.Pro25Leu (c.74C>T) is very rare (popmax 0.00154%, afr) (gnomAD).

What do computational predictors say about CCDC3 p.Pro25Leu (c.74C>T)?

AlphaMissense predicts likely pathogenic (score 0.8125) — an in-silico prediction, not a clinical call.

CCDC3 p.Pro25Leu

c.74C>T · VCV4828088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00154%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8125	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -10.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 4.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 103 kb · p 0.00074 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00154% African / African-American · 1/64,952 alleles

Filtering AF 7.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000336% 4/1,189,050 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00154%	64,952
European (non-Finnish)	0.000286%	349,471

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.Pro25Leu
Coding: c.74C>T
MANE Select: NM_031455
Type: single nucleotide variant
Location: chr10:13001497 (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-pro25leu (accessed [today's date]).

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