Is CCRL2 p.Trp251Cys (c.753G>T) pathogenic?

CCRL2 p.Trp251Cys (c.753G>T) is classified Uncertain significance in CCRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9228); Very rare (popmax 0.000254%, nfe).

How common is CCRL2 p.Trp251Cys (c.753G>T) in the general population?

CCRL2 p.Trp251Cys (c.753G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CCRL2 p.Trp251Cys (c.753G>T)?

AlphaMissense predicts likely pathogenic (score 0.9228) — an in-silico prediction, not a clinical call.

CCRL2 p.Trp251Cys

c.753G>T · VCV4222307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9228	likely pathogenic · top 1% in CCRL2
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -10.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,031 bp · p 0.057 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,180,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,890 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: CCRL2
Protein: p.Trp251Cys
Coding: c.753G>T
MANE Select: NM_003965
Type: single nucleotide variant
Location: chr3:46408832 (GRCh38)
Gene constraint: LOEUF 1.939 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 77.93

Full CCRL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCRL2 p.Ter345Ser Benign ★★ same type
CCRL2 c.-13+173T>A Uncertain significance ★ same type
CCRL2 c.-13+178A>T Uncertain significance ★ same type
CCRL2 c.-13+181C>T Uncertain significance ★ same type
CCRL2 p.Ala252Val Uncertain significance ★ ⚠ same type
CCRL2 p.Ala47Val Uncertain significance ★ ⚠ same type
CCRL2 p.Ala81Thr Uncertain significance ★ ⚠ same type
CCRL2 p.Arg144Lys 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/ccrl2-p-trp251cys (accessed [today's date]).

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