Is C3 p.Arg712Leu (c.2135G>T) pathogenic?

C3 p.Arg712Leu (c.2135G>T) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1347); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C3 p.Arg712Leu (c.2135G>T)?

C3 p.Arg712Leu (c.2135G>T) is associated with Inborn genetic diseases (ClinVar).

How common is C3 p.Arg712Leu (c.2135G>T) in the general population?

C3 p.Arg712Leu (c.2135G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C3 p.Arg712Leu (c.2135G>T)?

AlphaMissense predicts likely benign (score 0.1347) — an in-silico prediction, not a clinical call.

C3 p.Arg712Leu

c.2135G>T · VCV4217346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1347 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1347	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.81	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 -3.9	GERP -3.5
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	7.849	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C3
Protein: p.Arg712Leu
Coding: c.2135G>T
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6707186 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 712: the anaphylatoxin-like domain; a turn; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C3 p.Arg712His Uncertain significance ★★ ⚠ same residue
C3 p.Arg712Cys Uncertain significance ★ ⚠ same residue
C3 p.Ala1214Pro Uncertain significance ★★ ⚠ same condition
C3 p.Ala642Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala655Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala719Val Uncertain significance ★★ ⚠ same condition
C3 p.Arg1254His Uncertain significance ★★ ⚠ same condition
C3 p.Arg1393Gln 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-arg712leu (accessed [today's date]).

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