Is C1R p.Arg177His (c.530G>A) pathogenic?

C1R p.Arg177His (c.530G>A) is classified Likely benign in C1R (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0735); Ultra-rare (popmax 0.0258%, nfe).

How common is C1R p.Arg177His (c.530G>A) in the general population?

C1R p.Arg177His (c.530G>A) is ultra-rare (popmax 0.0258%, nfe) (gnomAD).

What do computational predictors say about C1R p.Arg177His (c.530G>A)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

C1R p.Arg177His

c.530G>A · VCV3769288

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0258%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -8.21	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 -4.9	GERP -3.7
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	5.025	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 0.0258% European (non-Finnish) · 108/417,992 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.0163% 127/780,778 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0258%	3,870
Finnishnot grpmax-eligible	0.011%	9,103
Admixed American	0.0102%	9,837
African / African-American	0.00676%	14,785
Remaining individualsnot grpmax-eligible	0.00284%	35,168
East Asian	0.00242%	41,270

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: C1R
Protein: p.Arg177His
Coding: c.530G>A
MANE Select: NM_001733
Type: single nucleotide variant
Location: chr12:7089628 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 177: a disulfide bond; the egf-like; calcium-binding domain

Full C1R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1R p.Arg301Pro Pathogenic ★★ ⚠ same type
C1R p.Asp290Gly Pathogenic/Likely pathogenic ★★ same type
C1R p.Cys338Arg Pathogenic ★★ same type
C1R p.Cys371Trp Pathogenic ★★ same type
C1R p.Gly297Asp Pathogenic/Likely pathogenic ★★ same type
C1R p.His642Gln Uncertain significance ★★ ⚠ same type
C1R p.Leu285Met Uncertain significance ★★ ⚠ same type
C1R p.Phe318Cys 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/c1r-p-arg177his (accessed [today's date]).

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