Is C3 p.Ala666Val (c.1997C>T) pathogenic?

C3 p.Ala666Val (c.1997C>T) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-06). AlphaMissense: likely benign (0.1045); Very rare (popmax 0.00133%, afr); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Ala666Val (c.1997C>T)?

C3 p.Ala666Val (c.1997C>T) is associated with atypical hemolytic-uremic syndrome with C3 anomaly, age related macular degeneration 9, complement component 3 deficiency (ClinVar).

How common is C3 p.Ala666Val (c.1997C>T) in the general population?

C3 p.Ala666Val (c.1997C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about C3 p.Ala666Val (c.1997C>T)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

C3 p.Ala666Val

c.1997C>T · VCV3584142

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.16	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 2.8	GERP 0.54, phastCons 0.88
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Overall 6.84e-05% 1/1,461,774 alleles · very rare

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.Ala666Val
Coding: c.1997C>T
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6707516 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 666: a disulfide bond

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

Disease context

atypical hemolytic-uremic syndrome with C3 anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 complement component 3 deficiency

Similar variants

C3 p.Ala666Gly Uncertain significance ★ ⚠ same residue
C3 p.Ala666= 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

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-ala666val (accessed [today's date]).

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