Is CRELD1 p.Ser222= (c.666A>G) pathogenic?

CRELD1 p.Ser222= (c.666A>G) is classified Likely benign in CRELD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-28). Very rare (popmax 0.0011%, nfe); Associated with atrioventricular septal defect, susceptibility to, 2.

What condition is associated with CRELD1 p.Ser222= (c.666A>G)?

CRELD1 p.Ser222= (c.666A>G) is associated with atrioventricular septal defect, susceptibility to, 2 (ClinVar).

How common is CRELD1 p.Ser222= (c.666A>G) in the general population?

CRELD1 p.Ser222= (c.666A>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

CRELD1 p.Ser222=

c.666A>G · rs1234487889 · VCV730776

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

atrioventricular septal defect, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -9.3	GERP -3.4
Overall
CADD	0.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,046 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	0.0011%	90,773

Remaining individuals 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: CRELD1
Protein: p.Ser222=
Coding: c.666A>G
MANE Select: NM_001077415
dbSNP: rs1234487889
Type: single nucleotide variant
Location: chr3:9941139 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68

Full CRELD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atrioventricular septal defect, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRELD1 c.1049-283C>T Uncertain significance ★★ same condition
CRELD1 c.1049-376T>G Uncertain significance ★★ same condition
CRELD1 c.1049-401C>T Uncertain significance ★★ same condition
CRELD1 p.Arg107Cys Uncertain significance ★★ ⚠ same condition
CRELD1 p.Arg175Gln Uncertain significance ★★ ⚠ same condition
CRELD1 p.Asn72Ser Uncertain significance ★★ ⚠ same condition
CRELD1 p.Cys221Arg Uncertain significance ★★ ⚠ same condition
CRELD1 p.Cys292Arg 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/creld1-p-ser222 (accessed [today's date]).

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