Is CCDC12 p.Ile99Met (c.297C>G) pathogenic?

CCDC12 p.Ile99Met (c.297C>G) is classified Uncertain significance in CCDC12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.2104); Very rare (popmax 0.00171%, amr).

How common is CCDC12 p.Ile99Met (c.297C>G) in the general population?

CCDC12 p.Ile99Met (c.297C>G) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about CCDC12 p.Ile99Met (c.297C>G)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

CCDC12 p.Ile99Met

c.297C>G · rs141076138 · VCV2526208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.527	indeterminate
SaProt	LLR -10.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -3.1
Regional constraint	o/e 0.94	unconstrained · MANE · 55 kb · p 0.41 · regional, not allelic
Overall
CADD	4.278	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 0.00171% Admixed American · 1/58,596 alleles

Overall 6.91e-05% 1/1,447,162 alleles · very 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: CCDC12
Protein: p.Ile99Met
Coding: c.297C>G
MANE Select: NM_001277074
dbSNP: rs141076138
Type: single nucleotide variant
Location: chr3:46923616 (GRCh38)
Gene constraint: LOEUF 1.568 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 6 PDB

Full CCDC12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NBEAL2 c.51+18C>T Benign/Likely benign ★★ same type
CCDC12 c.-3A>G Uncertain significance ★ same type
CCDC12 p.Ala134Ser Uncertain significance ★ ⚠ same type
CCDC12 p.Ala151Pro Uncertain significance ★ ⚠ same type
CCDC12 p.Ala3Val Uncertain significance ★ ⚠ same type
CCDC12 p.Ala93Ser Uncertain significance ★ ⚠ same type
CCDC12 p.Arg130Gln Uncertain significance ★ ⚠ same type
CCDC12 p.Arg26Pro 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/ccdc12-p-ile99met (accessed [today's date]).

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