Is CCRL2 p.Val53Ala (c.158T>C) pathogenic?

CCRL2 p.Val53Ala (c.158T>C) is classified Uncertain significance in CCRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.1923); Very rare (popmax 0.00667%, amr).

How common is CCRL2 p.Val53Ala (c.158T>C) in the general population?

CCRL2 p.Val53Ala (c.158T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CCRL2 p.Val53Ala (c.158T>C)?

AlphaMissense predicts likely benign (score 0.1923) — an in-silico prediction, not a clinical call.

CCRL2 p.Val53Ala

c.158T>C · rs369556399 · VCV3140112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1923	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -8.44	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 4.2	GERP -0.42, phastCons 0.82
Regional constraint	o/e 1.09	unconstrained · MANE · 1,031 bp · p 0.057 · regional, not allelic
Overall
CADD	16.09	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 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00353% 57/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
European (non-Finnish)	0.00441%	22,693
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Val53Ala
Coding: c.158T>C
MANE Select: NM_003965
dbSNP: rs369556399
Type: single nucleotide variant
Location: chr3:46408237 (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.Val53Ile Uncertain significance ★ ⚠ same residue
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

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-val53ala (accessed [today's date]).

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