Is CRELD1 p.Trp28Cys (c.84G>T) pathogenic?

CRELD1 p.Trp28Cys (c.84G>T) is classified Uncertain significance in CRELD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1836); Ultra-rare (popmax 0.0333%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRELD1 p.Trp28Cys (c.84G>T)?

CRELD1 p.Trp28Cys (c.84G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRELD1 p.Trp28Cys (c.84G>T) in the general population?

CRELD1 p.Trp28Cys (c.84G>T) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about CRELD1 p.Trp28Cys (c.84G>T)?

AlphaMissense predicts likely benign (score 0.1836) — an in-silico prediction, not a clinical call.

CRELD1 p.Trp28Cys

c.84G>T · VCV4234075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1836	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.68	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 3.2	GERP 0.19, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 10 kb · p 0.081 · regional, not allelic
Overall
CADD	20.3	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 0.0333% African / African-American · 25/74,966 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00161% 26/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	2,999
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: CRELD1
Protein: p.Trp28Cys
Coding: c.84G>T
MANE Select: NM_001077415
Type: single nucleotide variant
Location: chr3:9934522 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRELD1 p.Trp28Gly Uncertain significance ★ ⚠ same residue
CRELD1 c.460+1G>A Likely pathogenic ★★ same condition
CRELD1 p.Arg175Gln Uncertain significance ★★ ⚠ same condition
CRELD1 p.Cys221Arg Uncertain significance ★★ ⚠ same condition
CRELD1 p.Glu78Gln Uncertain significance ★★ ⚠ same condition
CRELD1 p.Gly164Ser Uncertain significance ★★ ⚠ same condition
CRELD1 p.Gly167Arg Uncertain significance ★★ ⚠ same condition
CRELD1 p.Gly283Arg 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-trp28cys (accessed [today's date]).

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