Is CCDC18 p.Leu448Phe (c.1342C>T) pathogenic?

CCDC18 p.Leu448Phe (c.1342C>T) is classified Uncertain significance in CCDC18 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: ambiguous (0.4219); Very rare (popmax 0.00136%, afr).

How common is CCDC18 p.Leu448Phe (c.1342C>T) in the general population?

CCDC18 p.Leu448Phe (c.1342C>T) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about CCDC18 p.Leu448Phe (c.1342C>T)?

AlphaMissense predicts ambiguous (score 0.4219) — an in-silico prediction, not a clinical call.

CCDC18 p.Leu448Phe

c.1342C>T · rs1451646714 · VCV2489359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4219	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -11.63	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 6	GERP 1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 95 kb · p 0.00026 · regional, not allelic
Overall
CADD	25.2	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 0.00136% African / African-American · 1/73,742 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000376% 6/1,596,158 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,742
European (non-Finnish)	0.000426%	234,960

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.Leu448Phe
Coding: c.1342C>T
MANE Select: NM_001378204
dbSNP: rs1451646714
Type: single nucleotide variant
Location: chr1:93212108 (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.Leu448Pro Likely benign same residue
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

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-leu448phe (accessed [today's date]).

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