Is C3 p.Ile348Val (c.1042A>G) pathogenic?

C3 p.Ile348Val (c.1042A>G) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1343); Very rare (popmax 0.00949%, nfe); Associated with complement component 3 deficiency.

What condition is associated with C3 p.Ile348Val (c.1042A>G)?

C3 p.Ile348Val (c.1042A>G) is associated with complement component 3 deficiency, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Ile348Val (c.1042A>G) in the general population?

C3 p.Ile348Val (c.1042A>G) is very rare (popmax 0.00949%, nfe) (gnomAD).

How is Complement component 3 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C3 p.Ile348Val (c.1042A>G)?

AlphaMissense predicts likely benign (score 0.1343) — an in-silico prediction, not a clinical call.

C3 p.Ile348Val

c.1042A>G · rs141737564 · VCV330331

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 3 deficiency

Computational evidence

Protein change
AlphaMissense	0.1343	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	23.7	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 0.00949% European (non-Finnish) · 112/1,179,990 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00719% 116/1,614,126 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00949%	10,536
Remaining individualsnot grpmax-eligible	0.0064%	15,626

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.Ile348Val
Coding: c.1042A>G
MANE Select: NM_000064
dbSNP: rs141737564
Type: single nucleotide variant
Location: chr19:6712585 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 348: a β-strand

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

Disease context

complement component 3 deficiency — 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

For Complement component 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

C3 p.Ile348= 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-ile348val (accessed [today's date]).

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