Is CCDC178 p.Arg730Thr (c.2189G>C) pathogenic?

CCDC178 p.Arg730Thr (c.2189G>C) is classified Uncertain significance in CCDC178 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.2054); Very rare (popmax 0.000934%, nfe).

How common is CCDC178 p.Arg730Thr (c.2189G>C) in the general population?

CCDC178 p.Arg730Thr (c.2189G>C) is very rare (popmax 0.000934%, nfe) (gnomAD).

What do computational predictors say about CCDC178 p.Arg730Thr (c.2189G>C)?

AlphaMissense predicts likely benign (score 0.2054) — an in-silico prediction, not a clinical call.

CCDC178 p.Arg730Thr

c.2189G>C · VCV3996759

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000934%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2054	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -2.8
Regional constraint	o/e 1.04	unconstrained · MANE · 474 kb · p 0.17 · regional, not allelic
Overall
CADD	2.16	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000934% European (non-Finnish) · 11/1,178,226 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000754% 11/1,458,164 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: CCDC178
Protein: p.Arg730Thr
Coding: c.2189G>C
MANE Select: NM_001105528
Type: single nucleotide variant
Location: chr18:33211945 (GRCh38)
Gene constraint: LOEUF 1.347 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.69

Full CCDC178 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC178 p.Lys515Arg Uncertain significance ★★ ⚠ same type
CCDC178 p.Ala216Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala261Gly Uncertain significance ★ ⚠ same type
CCDC178 p.Ala339Asp Uncertain significance ★ ⚠ same type
CCDC178 p.Ala339Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala375Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala563Thr Uncertain significance ★ ⚠ same type
CCDC178 p.Ala574Glu 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/ccdc178-p-arg730thr (accessed [today's date]).

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