Is C3 p.Leu10Met (c.28C>A) pathogenic?

C3 p.Leu10Met (c.28C>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.154); Ultra-rare (popmax 0.0159%, eas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Leu10Met (c.28C>A)?

C3 p.Leu10Met (c.28C>A) 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.Leu10Met (c.28C>A) in the general population?

C3 p.Leu10Met (c.28C>A) is ultra-rare (popmax 0.0159%, eas) (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.Leu10Met (c.28C>A)?

AlphaMissense predicts likely benign (score 0.154) — an in-silico prediction, not a clinical call.

C3 p.Leu10Met

c.28C>A · rs756577495 · VCV1063298

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.154 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.154	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -10.73	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	GERP 1.7, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,238 bp · p 0.45 · regional, not allelic
Overall
CADD	21.4	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 0.0159% East Asian · 7/43,988 alleles

Filtering AF 0.00739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00523%

Overall 0.000503% 8/1,589,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0159%	6,284
Remaining individualsnot grpmax-eligible	0.00162%	61,596

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.Leu10Met
Coding: c.28C>A
MANE Select: NM_000064
dbSNP: rs756577495
Type: single nucleotide variant
Location: chr19:6720562 (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

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

C3 p.Leu10= Likely benign ★ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G Likely pathogenic ★★ same condition
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

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-leu10met (accessed [today's date]).

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