Is C3 p.Pro314Leu (c.941C>T) pathogenic?

C3 p.Pro314Leu (c.941C>T) is classified Benign/Likely benign in C3 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1183); Common (popmax 20.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Pro314Leu (c.941C>T)?

C3 p.Pro314Leu (c.941C>T) is associated with atypical hemolytic-uremic syndrome, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

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.Pro314Leu (c.941C>T)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

C3 p.Pro314Leu

Q: How common is C3 p.Pro314Leu (c.941C>T) in the general population?

C3 p.Pro314Leu (c.941C>T) is common (popmax 20.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.941C>T · rs1047286 · VCV17057

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 20.8%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -3.11	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 5.2	GERP 0.48, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	13.32	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 20.8% European (non-Finnish) · 245,257/1,179,864 alleles

Filtering AF 20.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.7%

Overall 18.1% 291,273/1,613,434 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	21.7%	5
European (non-Finnish)grpmax	20.8%	5
Remaining individualsnot grpmax-eligible	17.6%	6
Finnishnot grpmax-eligible	17.2%	6
Middle Eastern	13.7%	7
South Asian	10%	10
Admixed American	8.32%	12
Amishnot grpmax-eligible	6.58%	15
African / African-American	3.48%	29
East Asian	0.0624%	1,603

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro314Leu
Coding: c.941C>T
MANE Select: NM_000064
dbSNP: rs1047286
Type: single nucleotide variant
Location: chr19:6713251 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 314: a UniProt-annotated variant site (in)

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 focal segmental glomerulosclerosis

For Atypical hemolytic uremic syndrome (Orphanet):

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

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C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition
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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-pro314leu (accessed [today's date]).

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