Is C3 p.Phe222Ile (c.664T>A) pathogenic?

C3 p.Phe222Ile (c.664T>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.7907); Ultra-rare (popmax 0.0388%, afr); Associated with age related macular degeneration 9.

What condition is associated with C3 p.Phe222Ile (c.664T>A)?

C3 p.Phe222Ile (c.664T>A) is associated with age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly, complement component 3 deficiency (ClinVar).

How common is C3 p.Phe222Ile (c.664T>A) in the general population?

C3 p.Phe222Ile (c.664T>A) is ultra-rare (popmax 0.0388%, afr) (gnomAD).

What do computational predictors say about C3 p.Phe222Ile (c.664T>A)?

AlphaMissense predicts likely pathogenic (score 0.7907) — an in-silico prediction, not a clinical call.

C3 p.Phe222Ile

c.664T>A · rs537531577 · VCV1362671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 9

Computational evidence

Protein change
AlphaMissense	0.7907	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.9	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 0.0388% African / African-American · 29/74,830 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00205% 33/1,613,266 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0388%	2,580
Admixed American	0.005%	19,993
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Phe222Ile
Coding: c.664T>A
MANE Select: NM_000064
dbSNP: rs537531577
Type: single nucleotide variant
Location: chr19:6714184 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 222: a β-strand

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

Similar variants

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
C3 c.683-3C>A Uncertain significance ★★ 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-phe222ile (accessed [today's date]).

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