Is C6 p.Glu393Ala (c.1178A>C) pathogenic?

C6 p.Glu393Ala (c.1178A>C) is classified Uncertain significance in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1255); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C6 p.Glu393Ala (c.1178A>C)?

C6 p.Glu393Ala (c.1178A>C) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Glu393Ala (c.1178A>C) in the general population?

C6 p.Glu393Ala (c.1178A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C6 p.Glu393Ala (c.1178A>C)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

C6 p.Glu393Ala

c.1178A>C · VCV4601547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -8.27	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 4.1	GERP 1.3, phastCons 0.78
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	14.87	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: C6
Protein: p.Glu393Ala
Coding: c.1178A>C
MANE Select: NM_000065
Type: single nucleotide variant
Location: chr5:41172338 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 393: an α-helix; the macpf domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C6 p.Glu393Gln Uncertain significance ★★ ⚠ same residue
C6 p.Glu393Lys Uncertain significance ★★ ⚠ same residue
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same condition
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same condition
C6 p.Ala500Ser Uncertain significance ★★ ⚠ same condition
C6 p.Arg108His Uncertain significance ★★ ⚠ same condition
C6 p.Arg145His Uncertain significance ★★ ⚠ same condition
C6 p.Arg150His Uncertain significance ★★ ⚠ 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/c6-p-glu393ala (accessed [today's date]).

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