Is CCDC18 p.Ile1306Phe (c.3916A>T) pathogenic?

CCDC18 p.Ile1306Phe (c.3916A>T) is classified Benign in CCDC18 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-19). AlphaMissense: likely benign (0.1364); Low-frequency (popmax 3.33%, mid); Associated with CCDC18-related disorder.

What condition is associated with CCDC18 p.Ile1306Phe (c.3916A>T)?

CCDC18 p.Ile1306Phe (c.3916A>T) is associated with CCDC18-related disorder (ClinVar).

How common is CCDC18 p.Ile1306Phe (c.3916A>T) in the general population?

CCDC18 p.Ile1306Phe (c.3916A>T) is low-frequency (popmax 3.33%, mid) (gnomAD).

What do computational predictors say about CCDC18 p.Ile1306Phe (c.3916A>T)?

AlphaMissense predicts likely benign (score 0.1364) — an in-silico prediction, not a clinical call.

CCDC18 p.Ile1306Phe

c.3916A>T · rs41292129 · VCV3038261

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1364 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.33%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CCDC18-related disorder

Computational evidence

Protein change
AlphaMissense	0.1364	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -7.48	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 3.6	GERP 0.41, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 95 kb · p 0.00026 · regional, not allelic
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I1305F vs ClinVar I1306F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.33% Middle Eastern · 199/5,984 alleles

Filtering AF 2.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.8%

Overall 2.5% 38,723/1,549,016 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	8.57%	12
Finnishnot grpmax-eligible	5.51%	18
Middle Easterngrpmax	3.33%	30
European (non-Finnish)	2.64%	38
Remaining individualsnot grpmax-eligible	2.29%	44
South Asian	2.29%	44
Ashkenazi Jewishnot grpmax-eligible	1.78%	56
Admixed American	1.6%	63
African / African-American	0.424%	236
East Asian	0.00734%	13,624

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile1306Phe
Coding: c.3916A>T
MANE Select: NM_001378204
dbSNP: rs41292129
Type: single nucleotide variant
Location: chr1:93270377 (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 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
CCDC18 p.Asn314= 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-ile1306phe (accessed [today's date]).

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