Is CCDC68 p.Arg41Leu (c.122G>T) pathogenic?

CCDC68 p.Arg41Leu (c.122G>T) is classified Uncertain significance in CCDC68 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.5945); Very rare (popmax 0.000425%, nfe).

How common is CCDC68 p.Arg41Leu (c.122G>T) in the general population?

CCDC68 p.Arg41Leu (c.122G>T) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about CCDC68 p.Arg41Leu (c.122G>T)?

AlphaMissense predicts likely pathogenic (score 0.5945) — an in-silico prediction, not a clinical call.

CCDC68 p.Arg41Leu

c.122G>T · VCV4221426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5945	likely pathogenic · top 7% in CCDC68
REVEL	0.23	benign-leaning
SaProt	LLR -4.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 38 kb · p 0.29 · regional, not allelic
Overall
CADD	24.9	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 0.000425% European (non-Finnish) · 5/1,177,070 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,457,468 alleles · very rare

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: CCDC68
Protein: p.Arg41Leu
Coding: c.122G>T
MANE Select: NM_025214
Type: single nucleotide variant
Location: chr18:54941079 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 81.20

Full CCDC68 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC68 p.Arg41Gln Uncertain significance ★ ⚠ same residue
CCDC68 p.Arg13Gly Uncertain significance ★ ⚠ same type
CCDC68 p.Arg208Ile Uncertain significance ★ ⚠ same type
CCDC68 p.Arg258Cys Uncertain significance ★ ⚠ same type
CCDC68 p.Arg258Gly Uncertain significance ★ ⚠ same type
CCDC68 p.Arg258His Uncertain significance ★ ⚠ same type
CCDC68 p.Arg258Ser Uncertain significance ★ ⚠ same type
CCDC68 p.Asn292Lys 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/ccdc68-p-arg41leu (accessed [today's date]).

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