Is C3 p.Leu9Pro (c.26T>C) pathogenic?

C3 p.Leu9Pro (c.26T>C) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2413); Ultra-rare (popmax 0.0919%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Leu9Pro (c.26T>C)?

C3 p.Leu9Pro (c.26T>C) is associated with atypical hemolytic-uremic syndrome, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Leu9Pro (c.26T>C) in the general population?

C3 p.Leu9Pro (c.26T>C) is ultra-rare (popmax 0.0919%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C3 p.Leu9Pro (c.26T>C)?

AlphaMissense predicts likely benign (score 0.2413) — an in-silico prediction, not a clinical call.

C3 p.Leu9Pro

c.26T>C · rs138214338 · VCV872465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2413 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0919%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.2413	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -11.73	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,238 bp · p 0.45 · regional, not allelic
Overall
CADD	21.0	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 0.0919% European (non-Finnish) · 1,073/1,167,446 alleles

Filtering AF 0.0873% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0854%

Overall 0.0699% 1,111/1,588,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0919%	1,088
Remaining individualsnot grpmax-eligible	0.0211%	4,736
Middle Eastern	0.0166%	6,042
African / African-American	0.0161%	6,215
Finnishnot grpmax-eligible	0.0144%	6,923
Admixed American	0.00536%	18,639

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: C3
Protein: p.Leu9Pro
Coding: c.26T>C
MANE Select: NM_000064
dbSNP: rs138214338
Type: single nucleotide variant
Location: chr19:6720564 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 atypical hemolytic-uremic syndrome with C3 anomaly complement component 3 deficiency C3 glomerulonephritis

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

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C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ same condition
C3 p.Ile1157Thr Pathogenic/Likely pathogenic ★★ ⚠ 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/c3-p-leu9pro (accessed [today's date]).

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