Is CCDC181 p.Arg395Pro (c.1184G>C) pathogenic?

CCDC181 p.Arg395Pro (c.1184G>C) is classified Uncertain significance in CCDC181 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: likely pathogenic (0.9521); Very rare (popmax 8.48e-05%, nfe).

How common is CCDC181 p.Arg395Pro (c.1184G>C) in the general population?

CCDC181 p.Arg395Pro (c.1184G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CCDC181 p.Arg395Pro (c.1184G>C)?

AlphaMissense predicts likely pathogenic (score 0.9521) — an in-silico prediction, not a clinical call.

CCDC181 p.Arg395Pro

c.1184G>C · rs200950920 · VCV2270141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9521	likely pathogenic · top 2% in CCDC181
REVEL	0.163	moderately benign-leaning
SaProt	LLR -15.33	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.1, phastCons 0.84
Regional constraint	o/e 0.89	unconstrained · MANE · 30 kb · p 0.0056 · regional, not allelic
Overall
CADD	25.4	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 8.48e-05% European (non-Finnish) · 1/1,179,846 alleles

Overall 6.84e-05% 1/1,461,330 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: CCDC181
Protein: p.Arg395Pro
Coding: c.1184G>C
MANE Select: NM_001300969
dbSNP: rs200950920
Type: single nucleotide variant
Location: chr1:169419044 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.92

Full CCDC181 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC181 p.Ala292Thr Uncertain significance ★ ⚠ same type
CCDC181 p.Ala414Pro Uncertain significance ★ ⚠ same type
CCDC181 p.Ala41Val Uncertain significance ★ ⚠ same type
CCDC181 p.Arg150Gln Uncertain significance ★ ⚠ same type
CCDC181 p.Arg298Cys Uncertain significance ★ ⚠ same type
CCDC181 p.Arg310Gln Uncertain significance ★ ⚠ same type
CCDC181 p.Arg416Gln Uncertain significance ★ ⚠ same type
CCDC181 p.Arg64Trp 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/ccdc181-p-arg395pro (accessed [today's date]).

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