Is CR2 p.Pro589Ser (c.1765C>T) pathogenic?

CR2 p.Pro589Ser (c.1765C>T) is classified Uncertain significance in CR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.1084); Very rare (popmax 6.2e-05%); Associated with Inborn genetic diseases.

What condition is associated with CR2 p.Pro589Ser (c.1765C>T)?

CR2 p.Pro589Ser (c.1765C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CR2 p.Pro589Ser (c.1765C>T) in the general population?

CR2 p.Pro589Ser (c.1765C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about CR2 p.Pro589Ser (c.1765C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

CR2 p.Pro589Ser

c.1765C>T · VCV4006554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.69	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 1.9	GERP 2, phastCons 0.005
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	15.83	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 6.2e-05%

Overall 6.2e-05% 1/1,613,962 alleles · very rare exomes 1/1,461,718 · genomes 0/152,244 · joint denominator

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: CR2
Protein: p.Pro589Ser
Coding: c.1765C>T
MANE Select: NM_001006658
Type: single nucleotide variant
Location: chr1:207472966 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 589: the sushi 9 domain

Full CR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CR2 p.Ala174Pro Uncertain significance ★★ ⚠ same condition
CR2 p.Ala3Ser Uncertain significance ★★ ⚠ same condition
CR2 p.Arg1063Cys Uncertain significance ★★ ⚠ same condition
CR2 p.Arg358Lys Uncertain significance ★★ ⚠ same condition
CR2 p.Arg643Cys Uncertain significance ★★ ⚠ same condition
CR2 p.Arg716Gln Uncertain significance ★★ same condition
CR2 p.Arg840Gly Uncertain significance ★★ ⚠ same condition
CR2 p.Arg987Lys Uncertain significance ★★ ⚠ same condition

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/cr2-p-pro589ser (accessed [today's date]).

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