Is CCDC6 p.Leu281Phe (c.843A>C) pathogenic?

CCDC6 p.Leu281Phe (c.843A>C) is classified Uncertain significance in CCDC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.2437); Absent from gnomAD v4.1.

How common is CCDC6 p.Leu281Phe (c.843A>C) in the general population?

CCDC6 p.Leu281Phe (c.843A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCDC6 p.Leu281Phe (c.843A>C)?

AlphaMissense predicts likely benign (score 0.2437) — an in-silico prediction, not a clinical call.

CCDC6 p.Leu281Phe

c.843A>C · rs2492613579 · VCV3139231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2437 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2437	likely benign
REVEL	0.576	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -3.5, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 8,310 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCDC6
Protein: p.Leu281Phe
Coding: c.843A>C
MANE Select: NM_005436
dbSNP: rs2492613579
Type: single nucleotide variant
Location: chr10:59812639 (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-leu281phe (accessed [today's date]).

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