Is CRELD2 p.Gln173Arg (c.518A>G) pathogenic?

CRELD2 p.Gln173Arg (c.518A>G) is classified Uncertain significance in CRELD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.059); Ultra-rare (popmax 0.0117%, amr).

How common is CRELD2 p.Gln173Arg (c.518A>G) in the general population?

CRELD2 p.Gln173Arg (c.518A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CRELD2 p.Gln173Arg (c.518A>G)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

CRELD2 p.Gln173Arg

c.518A>G · VCV4234091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.51	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 -2.6	GERP -2.5
Regional constraint	o/e 0.99	unconstrained · MANE · 8,534 bp · p 0.81 · regional, not allelic
Overall
CADD	0.386	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 0.0117% Admixed American · 7/60,020 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000548% 8/1,460,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,574
South Asian	0.0011%	91,078

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.Gln173Arg
Coding: c.518A>G
MANE Select: NM_024324
Type: single nucleotide variant
Location: chr22:49921687 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.63
Residue 173: a disulfide bond; the egf-like 1 domain

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-gln173arg (accessed [today's date]).

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