Is CCDC18 p.Val741Leu (c.2221G>C) pathogenic?

CCDC18 p.Val741Leu (c.2221G>C) is classified Uncertain significance in CCDC18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.1101); Ultra-rare (popmax 0.0509%, amr).

How common is CCDC18 p.Val741Leu (c.2221G>C) in the general population?

CCDC18 p.Val741Leu (c.2221G>C) is ultra-rare (popmax 0.0509%, amr) (gnomAD).

What do computational predictors say about CCDC18 p.Val741Leu (c.2221G>C)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

CCDC18 p.Val741Leu

c.2221G>C · VCV4649347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -5.49	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 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 95 kb · p 0.00026 · regional, not allelic
Overall
CADD	22.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V740L vs ClinVar V741L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0509% Admixed American · 29/56,950 alleles

Filtering AF 0.0364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0315%

Overall 0.00284% 45/1,584,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0509%	1,964
Remaining individualsnot grpmax-eligible	0.0114%	8,763
African / African-American	0.00142%	70,594
European (non-Finnish)	0.000686%	145,698

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: CCDC18
Protein: p.Val741Leu
Coding: c.2221G>C
MANE Select: NM_001378204
Type: single nucleotide variant
Location: chr1:93226378 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.83

Full CCDC18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC18 p.Cys430= Benign ★★ same type
CCDC18 p.Leu817= Benign ★★ same type
CCDC18 p.Pro108= Benign ★★ same type
CCDC18 p.Ala1077Val Uncertain significance ★ ⚠ same type
CCDC18 p.Ala1209Gly Uncertain significance ★ ⚠ same type
CCDC18 p.Ala1209Pro Uncertain significance ★ ⚠ same type
CCDC18 p.Ala1287Thr Uncertain significance ★ ⚠ same type
CCDC18 p.Ala241Thr 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/ccdc18-p-val741leu (accessed [today's date]).

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