Is C5 p.Val1093Ile (c.3277G>A) pathogenic?

C5 p.Val1093Ile (c.3277G>A) is classified Conflicting classifications of pathogenicity in C5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-16). AlphaMissense: likely benign (0.0673); Ultra-rare (popmax 0.01%, amr); Associated with Eculizumab, poor response to.

What condition is associated with C5 p.Val1093Ile (c.3277G>A)?

C5 p.Val1093Ile (c.3277G>A) is associated with Eculizumab, poor response to, complement component 5 deficiency (ClinVar).

How common is C5 p.Val1093Ile (c.3277G>A) in the general population?

C5 p.Val1093Ile (c.3277G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about C5 p.Val1093Ile (c.3277G>A)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

C5 p.Val1093Ile

c.3277G>A · rs371131390 · VCV1443344

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Eculizumab, poor response to

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -5.14	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 -3.4	GERP -3.7
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	0.159	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 0.01% Admixed American · 6/59,926 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.00187% 30/1,600,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,988
East Asian	0.00671%	14,901
African / African-American	0.00536%	18,657
South Asian	0.00331%	30,192
Remaining individualsnot grpmax-eligible	0.00161%	61,968
European (non-Finnish)	0.00111%	89,890

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: C5
Protein: p.Val1093Ile
Coding: c.3277G>A
MANE Select: NM_001735
dbSNP: rs371131390
Type: single nucleotide variant
Location: chr9:120982768 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 1093: a disulfide bond; a UniProt-annotated variant site (in c5d)

Full C5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Eculizumab, poor response to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement component 5 deficiency

Similar variants

C5 p.Val1093Leu Uncertain significance ★ ⚠ same residue
C5 c.2257+1G>A Likely pathogenic ★★ same condition
C5 c.4679-2A>G Likely pathogenic ★★ same condition
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same condition
C5 p.Gln19Ter Pathogenic ★★ same condition
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same condition
C5 c.2059+3A>G Uncertain significance ★★ same condition
C5 c.4081-6A>G 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/c5-p-val1093ile (accessed [today's date]).

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