Is CRELD2 p.Val231Met (c.691G>A) pathogenic?

CRELD2 p.Val231Met (c.691G>A) is classified Uncertain significance in CRELD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). AlphaMissense: likely benign (0.1281); Very rare (popmax 8.6e-05%, nfe).

How common is CRELD2 p.Val231Met (c.691G>A) in the general population?

CRELD2 p.Val231Met (c.691G>A) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about CRELD2 p.Val231Met (c.691G>A)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

CRELD2 p.Val231Met

c.691G>A · rs2519323267 · VCV2536871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 8,534 bp · p 0.81 · regional, not allelic
Overall
CADD	22.7	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 8.6e-05% European (non-Finnish) · 1/1,162,202 alleles

Overall 7.02e-05% 1/1,423,782 alleles · very rare

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.Val231Met
Coding: c.691G>A
MANE Select: NM_024324
dbSNP: rs2519323267
Type: single nucleotide variant
Location: chr22:49923236 (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-val231met (accessed [today's date]).

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