Is C1RL p.Ala73Pro (c.217G>C) pathogenic?

C1RL p.Ala73Pro (c.217G>C) is classified Uncertain significance in C1RL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). AlphaMissense: likely pathogenic (0.6476); Rare (popmax 0.528%, mid).

How common is C1RL p.Ala73Pro (c.217G>C) in the general population?

C1RL p.Ala73Pro (c.217G>C) is rare (popmax 0.528%, mid) (gnomAD).

What do computational predictors say about C1RL p.Ala73Pro (c.217G>C)?

AlphaMissense predicts likely pathogenic (score 0.6476) — an in-silico prediction, not a clinical call.

C1RL p.Ala73Pro

c.217G>C · rs201343174 · VCV2273789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6476 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.528%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6476	likely pathogenic
REVEL	0.355	indeterminate
SaProt	LLR -12.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.015 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.528% Middle Eastern · 32/6,058 alleles

Filtering AF 0.385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.335%

Overall 0.0299% 483/1,614,250 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.528%	189
Remaining individualsnot grpmax-eligible	0.088%	1,136
Admixed American	0.065%	1,539
European (non-Finnish)	0.0266%	3,758
South Asian	0.0263%	3,795
African / African-American	0.024%	4,171
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Ala73Pro
Coding: c.217G>C
MANE Select: NM_016546
dbSNP: rs201343174
Type: single nucleotide variant
Location: chr12:7108334 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 73: the cub 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.Ala95Pro Uncertain significance ★ ⚠ same type
C1RL p.Arg136Trp Uncertain significance ★ ⚠ same type
C1RL p.Arg276Lys 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-ala73pro (accessed [today's date]).

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