Is CCDC18 p.Leu448Pro (c.1343T>C) pathogenic?

CCDC18 p.Leu448Pro (c.1343T>C) is classified Likely benign in CCDC18 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-05). AlphaMissense: likely pathogenic (0.9697); Low-frequency (popmax 1.14%, sas); Associated with CCDC18-related disorder.

What condition is associated with CCDC18 p.Leu448Pro (c.1343T>C)?

CCDC18 p.Leu448Pro (c.1343T>C) is associated with CCDC18-related disorder (ClinVar).

How common is CCDC18 p.Leu448Pro (c.1343T>C) in the general population?

CCDC18 p.Leu448Pro (c.1343T>C) is low-frequency (popmax 1.14%, sas) (gnomAD).

What do computational predictors say about CCDC18 p.Leu448Pro (c.1343T>C)?

AlphaMissense predicts likely pathogenic (score 0.9697) — an in-silico prediction, not a clinical call.

CCDC18 p.Leu448Pro

c.1343T>C · rs200393545 · VCV3044139

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9697 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CCDC18-related disorder

Computational evidence

Protein change
AlphaMissense	0.9697	likely pathogenic · top 1% in CCDC18
REVEL	0.291	indeterminate
SaProt	LLR -17.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 95 kb · p 0.00026 · regional, not allelic
Overall
CADD	27.0	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 1.14% South Asian · 987/86,736 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.0749% 1,197/1,598,068 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.14%	88
Middle Eastern	0.217%	461
Remaining individualsnot grpmax-eligible	0.0873%	1,145
European (non-Finnish)	0.0117%	8,581
Admixed American	0.00539%	18,544
East Asian	0.00451%	22,149
Finnishnot grpmax-eligible	0.00156%	63,898

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.Leu448Pro
Coding: c.1343T>C
MANE Select: NM_001378204
dbSNP: rs200393545
Type: single nucleotide variant
Location: chr1:93212109 (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

Disease context

CCDC18-related disorder

Similar variants

CCDC18 p.Leu448Phe Uncertain significance ★ ⚠ same residue
CCDC18 c.2982-6T>C Likely benign same condition
CCDC18 c.569+9A>G Benign same condition
CCDC18 p.Ala153= Likely benign same condition
CCDC18 p.Arg1108= Benign same condition
CCDC18 p.Arg1108Ser Benign same condition
CCDC18 p.Arg1281= Benign same condition
CCDC18 p.Arg429Cys Benign same condition

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-leu448pro (accessed [today's date]).

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