Is C1RL p.Arg321Leu (c.962G>T) pathogenic?

C1RL p.Arg321Leu (c.962G>T) is classified Uncertain significance in C1RL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.2162); Rare (popmax 0.582%, eas).

How common is C1RL p.Arg321Leu (c.962G>T) in the general population?

C1RL p.Arg321Leu (c.962G>T) is rare (popmax 0.582%, eas) (gnomAD).

What do computational predictors say about C1RL p.Arg321Leu (c.962G>T)?

AlphaMissense predicts likely benign (score 0.2162) — an in-silico prediction, not a clinical call.

C1RL p.Arg321Leu

c.962G>T · VCV4217185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2162 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.582%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2162	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -12.36	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 2.7	GERP 0.82, phastCons 0.95
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.015 · regional, not allelic
Overall
CADD	21.5	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 0.582% East Asian · 260/44,704 alleles

Filtering AF 0.524% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.501%

Overall 0.0167% 267/1,599,656 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.582%	172
Remaining individualsnot grpmax-eligible	0.00485%	20,626
South Asian	0.00337%	29,645
European (non-Finnish)	8.54e-05%	1,171,354

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.Arg321Leu
Coding: c.962G>T
MANE Select: NM_016546
Type: single nucleotide variant
Location: chr12:7096893 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 321: the peptidase s1 domain

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

Similar variants

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
C1RL p.Arg136Trp 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-arg321leu (accessed [today's date]).

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