Is CCDC6 p.Leu385Val (c.1153C>G) pathogenic?

CCDC6 p.Leu385Val (c.1153C>G) is classified Uncertain significance in CCDC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1484); Ultra-rare (popmax 0.0773%, afr).

How common is CCDC6 p.Leu385Val (c.1153C>G) in the general population?

CCDC6 p.Leu385Val (c.1153C>G) is ultra-rare (popmax 0.0773%, afr) (gnomAD).

What do computational predictors say about CCDC6 p.Leu385Val (c.1153C>G)?

AlphaMissense predicts likely benign (score 0.1484) — an in-silico prediction, not a clinical call.

CCDC6 p.Leu385Val

c.1153C>G · VCV4221345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1484 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0773%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1484	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.38	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 2.1	GERP -2.5, phastCons 0.97
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.59 · regional, not allelic
Overall
CADD	17.06	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 0.0773% African / African-American · 58/75,060 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0556%

Overall 0.00409% 66/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0773%	1,294
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Admixed American	0.00167%	60,028
European (non-Finnish)	0.000254%	393,255

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: CCDC6
Protein: p.Leu385Val
Coding: c.1153C>G
MANE Select: NM_005436
Type: single nucleotide variant
Location: chr10:59794550 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 76.03 · 2 PDB

Full CCDC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC6 p.Leu206= Benign ★★ same type
CCDC6 p.Ala13Thr Uncertain significance ★ ⚠ same type
CCDC6 p.Arg197Gln Uncertain significance ★ ⚠ same type
CCDC6 p.Arg271Gln Uncertain significance ★ ⚠ same type
CCDC6 p.Arg298Thr Uncertain significance ★ ⚠ same type
CCDC6 p.Arg415Gln Uncertain significance ★ ⚠ same type
CCDC6 p.Asn267Ser Uncertain significance ★ ⚠ same type
CCDC6 p.Cys319Ser 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/ccdc6-p-leu385val (accessed [today's date]).

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