Is C1R p.Lys235Arg (c.704A>G) pathogenic?

C1R p.Lys235Arg (c.704A>G) is classified Likely benign in C1R (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0854); Rare (popmax 0.283%, sas).

How common is C1R p.Lys235Arg (c.704A>G) in the general population?

C1R p.Lys235Arg (c.704A>G) is rare (popmax 0.283%, sas) (gnomAD).

What do computational predictors say about C1R p.Lys235Arg (c.704A>G)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

C1R p.Lys235Arg

c.704A>G · rs763297354 · VCV1335096

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.283%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.07	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 2.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	17.68	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 0.283% South Asian · 211/74,608 alleles

Filtering AF 0.252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.239%

Overall 0.0337% 263/780,588 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.283%	354
Remaining individualsnot grpmax-eligible	0.0341%	2,932
European (non-Finnish)	0.00933%	10,715
Admixed American	0.00169%	59,006

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.Lys235Arg
Coding: c.704A>G
MANE Select: NM_001733
dbSNP: rs763297354
Type: single nucleotide variant
Location: chr12:7089357 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 235: the cub 2 domain; a β-strand

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-lys235arg (accessed [today's date]).

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