Is C1RL p.Arg329His (c.986G>A) pathogenic?

C1RL p.Arg329His (c.986G>A) is classified Uncertain significance in C1RL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0571); Very rare (popmax 0.00113%, sas).

How common is C1RL p.Arg329His (c.986G>A) in the general population?

C1RL p.Arg329His (c.986G>A) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about C1RL p.Arg329His (c.986G>A)?

AlphaMissense predicts likely benign (score 0.0571) — an in-silico prediction, not a clinical call.

C1RL p.Arg329His

c.986G>A · VCV4217188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0571	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.12	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 -2.8	GERP -3
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.015 · regional, not allelic
Overall
CADD	7.149	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00113% South Asian · 1/88,662 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000375% 6/1,599,544 alleles · very rare exomes 5/1,447,364 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,662
European (non-Finnish)	0.000427%	234,346

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.Arg329His
Coding: c.986G>A
MANE Select: NM_016546
Type: single nucleotide variant
Location: chr12:7096869 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 329: the peptidase s1 domain

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

Similar variants

C1RL p.Arg329Cys 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-arg329his (accessed [today's date]).

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