Is C3AR1 p.Ile59Val (c.175A>G) pathogenic?

C3AR1 p.Ile59Val (c.175A>G) is classified Likely benign in C3AR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0589); Very rare (popmax 0.000424%, nfe).

How common is C3AR1 p.Ile59Val (c.175A>G) in the general population?

C3AR1 p.Ile59Val (c.175A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about C3AR1 p.Ile59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

C3AR1 p.Ile59Val

c.175A>G · VCV4217355

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -4.40	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 0.34	GERP 0.025, phastCons 0.019
Regional constraint	o/e 0.99	unconstrained · MANE · 1,445 bp · p 0.85 · regional, not allelic
Overall
CADD	5.461	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 0.000424% European (non-Finnish) · 5/1,179,952 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,012
European (non-Finnish)grpmax	0.000424%	235,990

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: C3AR1
Protein: p.Ile59Val
Coding: c.175A>G
MANE Select: NM_004054
Type: single nucleotide variant
Location: chr12:8060011 (GRCh38)
Gene constraint: LOEUF 1.58 · pLI 0.32 (gnomAD)
Structure: AlphaFold pLDDT 68.68 · 19 PDB
Residue 59: an α-helix

Full C3AR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C3AR1 p.Pro76Ala Uncertain significance ★★ ⚠ same type
C3AR1 p.Tyr90= Likely benign ★★ same type
C3AR1 p.Val136Ala Benign/Likely benign ★★ ⚠ same type
C3AR1 p.Val47Gly Benign ★★ ⚠ same type
C3AR1 c.-8G>A Uncertain significance ★ same type
C3AR1 p.Ala150Asp Uncertain significance ★ ⚠ same type
C3AR1 p.Ala288Asp Uncertain significance ★ ⚠ same type
C3AR1 p.Ala2Val Uncertain significance ★ ⚠ same type

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/c3ar1-p-ile59val (accessed [today's date]).

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