Is C1RL p.Arg368Cys (c.1102C>T) pathogenic?

C1RL p.Arg368Cys (c.1102C>T) is classified Uncertain significance in C1RL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.105); Rare (popmax 0.116%, mid).

How common is C1RL p.Arg368Cys (c.1102C>T) in the general population?

C1RL p.Arg368Cys (c.1102C>T) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about C1RL p.Arg368Cys (c.1102C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

C1RL p.Arg368Cys

c.1102C>T · rs139459588 · VCV3135815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -3.7, phastCons 0.034
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.015 · regional, not allelic
Overall
CADD	17.71	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 0.116% Middle Eastern · 7/6,050 alleles

Filtering AF 0.0768% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0708%

Overall 0.0414% 666/1,610,406 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	864
South Asian	0.0928%	1,078
European (non-Finnish)	0.0452%	2,214
Remaining individualsnot grpmax-eligible	0.0417%	2,397
Admixed American	0.0134%	7,471
African / African-American	0.0107%	9,374
East Asian	0.00223%	44,824

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: C1RL
Protein: p.Arg368Cys
Coding: c.1102C>T
MANE Select: NM_016546
dbSNP: rs139459588
Type: single nucleotide variant
Location: chr12:7096753 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 368: the peptidase s1 domain

Full C1RL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1RL p.Arg368His Uncertain significance ★ ⚠ same residue
C1RL p.Ala183Val Uncertain significance ★ ⚠ same type
C1RL p.Ala202Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala271Asp Uncertain significance ★ ⚠ same type
C1RL p.Ala404Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala45Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala73Pro Uncertain significance ★ ⚠ same type
C1RL p.Ala95Pro 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/c1rl-p-arg368cys (accessed [today's date]).

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