Is CRELD2 p.Ser144Pro (c.430T>C) pathogenic?

CRELD2 p.Ser144Pro (c.430T>C) is classified Uncertain significance in CRELD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely benign (0.0944); Ultra-rare (popmax 0.01%, amr).

How common is CRELD2 p.Ser144Pro (c.430T>C) in the general population?

CRELD2 p.Ser144Pro (c.430T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CRELD2 p.Ser144Pro (c.430T>C)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

CRELD2 p.Ser144Pro

c.430T>C · rs1167175613 · VCV2308340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -3.31	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 -0.51	GERP -2.4
Regional constraint	o/e 0.99	unconstrained · MANE · 8,534 bp · p 0.81 · regional, not allelic
Overall
CADD	15.93	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 0.01% Admixed American · 6/59,966 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,612,480 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,994
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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.Ser144Pro
Coding: c.430T>C
MANE Select: NM_024324
dbSNP: rs1167175613
Type: single nucleotide variant
Location: chr22:49921599 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.63
Residue 144: 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-ser144pro (accessed [today's date]).

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