Is CROCC p.Arg1463Pro (c.4388G>C) pathogenic?

CROCC p.Arg1463Pro (c.4388G>C) is classified Uncertain significance in CROCC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.0817); Ultra-rare (popmax 0.041%, amr).

How common is CROCC p.Arg1463Pro (c.4388G>C) in the general population?

CROCC p.Arg1463Pro (c.4388G>C) is ultra-rare (popmax 0.041%, amr) (gnomAD).

What do computational predictors say about CROCC p.Arg1463Pro (c.4388G>C)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

CROCC p.Arg1463Pro

c.4388G>C · rs1302082712 · VCV2410497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -5.25	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 1.1	GERP 1.1, phastCons 0.4
Regional constraint	o/e 0.95	unconstrained · MANE · 18 kb · p 0.057 · regional, not allelic
Overall
CADD	12.91	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 0.041% Admixed American · 11/26,824 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0177%

Overall 0.00111% 15/1,352,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.041%	2,439
Ashkenazi Jewishnot grpmax-eligible	0.00961%	10,409
Remaining individualsnot grpmax-eligible	0.00198%	50,522
European (non-Finnish)	9.46e-05%	1,057,326

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: CROCC
Protein: p.Arg1463Pro
Coding: c.4388G>C
MANE Select: NM_014675
dbSNP: rs1302082712
Type: single nucleotide variant
Location: chr1:16961113 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 2 PDB
Residue 1463: the 'disordered' region

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

Similar variants

CROCC p.Arg1463Trp Uncertain significance ★ ⚠ same residue
CROCC p.Arg1094Trp Uncertain significance ★★ ⚠ same type
CROCC p.Asp1119His Uncertain significance ★★ ⚠ same type
CROCC p.Gly486Arg Uncertain significance ★★ ⚠ same type
CROCC p.Arg1729Gln Likely benign ★★ same type
CROCC p.Arg1908Cys Benign ★★ ⚠ same type
CROCC p.Arg675His Benign ★★ same type
CROCC p.Arg691His Benign ★★ 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/crocc-p-arg1463pro (accessed [today's date]).

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