Is CCDC121 p.Arg27Pro (c.80G>C) pathogenic?

CCDC121 p.Arg27Pro (c.80G>C) is classified Uncertain significance in CCDC121 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: ambiguous (0.5502); Ultra-rare (popmax 0.0493%, mid).

How common is CCDC121 p.Arg27Pro (c.80G>C) in the general population?

CCDC121 p.Arg27Pro (c.80G>C) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CCDC121 p.Arg27Pro (c.80G>C)?

AlphaMissense predicts ambiguous (score 0.5502) — an in-silico prediction, not a clinical call.

CCDC121 p.Arg27Pro

c.80G>C · VCV3828104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5502	ambiguous · top 3% in CCDC121
REVEL	0.157	moderately benign-leaning
SaProt	LLR -13.21	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.1
Regional constraint	o/e 0.78	unconstrained · MANE · 833 bp · p 0.00015 · regional, not allelic
Overall
CADD	0.253	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 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00112% 18/1,613,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
African / African-American	0.016%	6,237
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	8.47e-05%	1,180,018

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: CCDC121
Protein: p.Arg27Pro
Coding: c.80G>C
MANE Select: NM_024584
Type: single nucleotide variant
Location: chr2:27627720 (GRCh38)
Gene constraint: LOEUF 1.848 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 87.88

Full CCDC121 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC121 c.-116T>C Uncertain significance ★ same type
CCDC121 c.-119+251C>T Uncertain significance ★ same type
CCDC121 c.-119+257G>A Uncertain significance ★ same type
CCDC121 c.-119+287C>T Uncertain significance ★ same type
CCDC121 c.-119+292C>G Uncertain significance ★ same type
CCDC121 c.-119+298T>C Uncertain significance ★ same type
CCDC121 c.-119+337C>A Uncertain significance ★ same type
CCDC121 c.-119+385C>G 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/ccdc121-p-arg27pro (accessed [today's date]).

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