Is CR2 p.Pro462fs (c.1385del) pathogenic?

CR2 p.Pro462fs (c.1385del) is classified Likely pathogenic in CR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-06). Very rare (popmax 0.000124%); Associated with CR2-related disorder.

What condition is associated with CR2 p.Pro462fs (c.1385del)?

CR2 p.Pro462fs (c.1385del) is associated with CR2-related disorder (ClinVar).

How common is CR2 p.Pro462fs (c.1385del) in the general population?

CR2 p.Pro462fs (c.1385del) is very rare (popmax 0.000124%) (gnomAD).

CR2 p.Pro462fs

c.1385del · VCV4930297

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Conditions

CR2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.46	GERP -3.3

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000124%

Overall 0.000124% 2/1,613,626 alleles · very rare exomes 2/1,461,536 · genomes 0/152,090 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Remaining individualsnot grpmax-eligible	0.0016%	62,476

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro462fs
Coding: c.1385del
MANE Select: NM_001006658
Type: Deletion
Location: chr1:207470895 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 462: the sushi 7 domain

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

Disease context

CR2-related disorder

Similar variants

CR2 p.Pro208fs Pathogenic/Likely pathogenic ★★ same condition
CR2 c.3089-1G>A Likely pathogenic ★★ same condition
CR2 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Arg368Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Val375fs Likely pathogenic ★★ same condition
CR2 c.3088+1G>T Likely pathogenic ★ same condition
CR2 p.Gly1003fs Likely pathogenic ★ same condition
CR2 p.Arg220Gln Conflicting classifications of pathogenicity ★ ⚠ 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-pro462fs (accessed [today's date]).

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