Is C3 p.Ala1437= (c.4311C>T) pathogenic?

C3 p.Ala1437= (c.4311C>T) is classified Benign/Likely benign in C3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Common (popmax 9.52%, sas) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 9.

What condition is associated with C3 p.Ala1437= (c.4311C>T)?

C3 p.Ala1437= (c.4311C>T) is associated with age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly, complement component 3 deficiency (ClinVar).

C3 p.Ala1437=

Q: How common is C3 p.Ala1437= (c.4311C>T) in the general population?

C3 p.Ala1437= (c.4311C>T) is common (popmax 9.52%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4311C>T · rs7951 · VCV330285

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 9.52%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

age related macular degeneration 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -3.5
Overall
CADD	2.719	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.52% South Asian · 8,664/91,056 alleles

Filtering AF 9.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.28%

Overall 7.84% 126,534/1,613,528 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	11.7%	9
Amishnot grpmax-eligible	11.6%	9
South Asiangrpmax	9.52%	11
African / African-American	9.42%	11
Ashkenazi Jewishnot grpmax-eligible	9.38%	11
East Asian	9.32%	11
Middle Eastern	8.3%	12
Remaining individualsnot grpmax-eligible	8.15%	12
European (non-Finnish)	7.37%	14
Admixed American	6.19%	16

Finnish 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.Ala1437=
Coding: c.4311C>T
MANE Select: NM_000064
dbSNP: rs7951
Type: single nucleotide variant
Location: chr19:6681980 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1437: a disulfide bond

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

Disease context

Also linked: atypical hemolytic-uremic syndrome with C3 anomaly complement component 3 deficiency C3 glomerulonephritis atypical hemolytic-uremic syndrome

Similar variants

C3 p.Ala1437Val Uncertain significance ★★ 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-ala1437 (accessed [today's date]).

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