Is CCRL2 p.Val157Ile (c.469G>A) pathogenic?

CCRL2 p.Val157Ile (c.469G>A) is classified Uncertain significance in CCRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0961); Very rare (popmax 0.00415%, nfe).

How common is CCRL2 p.Val157Ile (c.469G>A) in the general population?

CCRL2 p.Val157Ile (c.469G>A) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about CCRL2 p.Val157Ile (c.469G>A)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

CCRL2 p.Val157Ile

c.469G>A · VCV4222305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.34	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 0.051	GERP -3.6, phastCons 0.001
Regional constraint	o/e 1.09	unconstrained · MANE · 1,031 bp · p 0.057 · regional, not allelic
Overall
CADD	0.25	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 0.00415% European (non-Finnish) · 49/1,179,968 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00322% 52/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,081
Admixed American	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Val157Ile
Coding: c.469G>A
MANE Select: NM_003965
Type: single nucleotide variant
Location: chr3:46408548 (GRCh38)
Gene constraint: LOEUF 1.939 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 77.93
Residue 157: a disulfide bond

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-val157ile (accessed [today's date]).

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