Is CCDC115 p.Arg142Gln (c.425G>A) pathogenic?

CCDC115 p.Arg142Gln (c.425G>A) is classified Uncertain significance in CCDC115 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.0329%, mid); Associated with CCDC115-CDG.

What condition is associated with CCDC115 p.Arg142Gln (c.425G>A)?

CCDC115 p.Arg142Gln (c.425G>A) is associated with CCDC115-CDG (ClinVar).

How common is CCDC115 p.Arg142Gln (c.425G>A) in the general population?

CCDC115 p.Arg142Gln (c.425G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is CCDC115-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CCDC115 p.Arg142Gln (c.425G>A)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CCDC115 p.Arg142Gln

c.425G>A · VCV3391371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CCDC115-CDG

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -6.01	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 -0.56	phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 3,002 bp · p 0.28 · regional, not allelic
Overall
CADD	16.75	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0013% 21/1,613,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.00136%	73,750
African / African-American	0.00133%	74,908
South Asian	0.0011%	91,070

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: CCDC115
Protein: p.Arg142Gln
Coding: c.425G>A
MANE Select: NM_032357
Type: single nucleotide variant
Location: chr2:130340913 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.32

Full CCDC115 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CCDC115-CDG — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CCDC115-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VMA22 p.Leu31Ser Pathogenic ★★ same condition
VMA22 p.Arg102Gln Uncertain significance ★★ ⚠ same condition
CCDC115 p.Arg157His Uncertain significance ★ ⚠ same condition
VMA22 p.Arg157Cys Uncertain significance ★ ⚠ same condition
VMA22 p.Glu36Asp Uncertain significance ★ ⚠ same condition
VMA22 p.Ile151Leu Uncertain significance ★ ⚠ same condition
CCDC115 p.Asp11Tyr Pathogenic same condition
VMA22 p.Glu76fs Pathogenic ★ 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/ccdc115-p-arg142gln (accessed [today's date]).

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