Is CRELD2 p.Arg5Cys (c.13C>T) pathogenic?

CRELD2 p.Arg5Cys (c.13C>T) is classified Uncertain significance in CRELD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: ambiguous (0.3827); Ultra-rare (popmax 0.0364%, amr).

How common is CRELD2 p.Arg5Cys (c.13C>T) in the general population?

CRELD2 p.Arg5Cys (c.13C>T) is ultra-rare (popmax 0.0364%, amr) (gnomAD).

What do computational predictors say about CRELD2 p.Arg5Cys (c.13C>T)?

AlphaMissense predicts ambiguous (score 0.3827) — an in-silico prediction, not a clinical call.

CRELD2 p.Arg5Cys

c.13C>T · rs1004117296 · VCV2561200

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3827	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -2.1, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 8,534 bp · p 0.81 · regional, not allelic
Overall
CADD	14.34	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 0.0364% Admixed American · 9/24,738 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.000867% 11/1,268,294 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0364%	2,749
Remaining individualsnot grpmax-eligible	0.0021%	47,568
European (non-Finnish)	0.000101%	993,502

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: CRELD2
Protein: p.Arg5Cys
Coding: c.13C>T
MANE Select: NM_024324
dbSNP: rs1004117296
Type: single nucleotide variant
Location: chr22:49918782 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.63

Full CRELD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRELD2 p.Ala236= Benign ★★ same type
CRELD2 p.Cys294= Benign/Likely benign ★★ same type
CRELD2 p.Gly162= Benign ★★ same type
CRELD2 c.593-181G>T Uncertain significance ★ same type
CRELD2 c.593-202A>T Uncertain significance ★ same type
CRELD2 c.593-208G>T Uncertain significance ★ same type
CRELD2 c.593-222C>T Uncertain significance ★ same type
CRELD2 c.593-228G>A 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/creld2-p-arg5cys (accessed [today's date]).

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