Is C1R p.Pro100Leu (c.299C>T) pathogenic?

C1R p.Pro100Leu (c.299C>T) is classified Uncertain significance in C1R (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely benign (0.3107); Ultra-rare (popmax 0.0226%, mid).

How common is C1R p.Pro100Leu (c.299C>T) in the general population?

C1R p.Pro100Leu (c.299C>T) is ultra-rare (popmax 0.0226%, mid) (gnomAD).

What do computational predictors say about C1R p.Pro100Leu (c.299C>T)?

AlphaMissense predicts likely benign (score 0.3107) — an in-silico prediction, not a clinical call.

C1R p.Pro100Leu

c.299C>T · VCV3895995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3107 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3107	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -12.99	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 10	GERP 1.7, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	24.3	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 0.0226% Middle Eastern · 1/4,430 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00166%

Overall 0.00211% 16/757,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0226%	4,430
European (non-Finnish)	0.00345%	28,987
Remaining individualsnot grpmax-eligible	0.00291%	34,342

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.Pro100Leu
Coding: c.299C>T
MANE Select: NM_001733
Type: single nucleotide variant
Location: chr12:7090181 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 100: the cub 1 domain

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

Similar variants

C1R p.Pro100= Benign ★ same residue
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

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-pro100leu (accessed [today's date]).

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