Is CCRL2 p.Ile16Thr (c.47T>C) pathogenic?

CCRL2 p.Ile16Thr (c.47T>C) is classified Uncertain significance in CCRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: ambiguous (0.3829); Ultra-rare (popmax 0.0117%, nfe).

How common is CCRL2 p.Ile16Thr (c.47T>C) in the general population?

CCRL2 p.Ile16Thr (c.47T>C) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

What do computational predictors say about CCRL2 p.Ile16Thr (c.47T>C)?

AlphaMissense predicts ambiguous (score 0.3829) — an in-silico prediction, not a clinical call.

CCRL2 p.Ile16Thr

c.47T>C · VCV3264651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3829	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -5.37	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.64, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,031 bp · p 0.057 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% European (non-Finnish) · 137/1,175,134 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00943%

Overall 0.00923% 148/1,603,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0117%	8,578
Remaining individualsnot grpmax-eligible	0.00805%	12,422
South Asian	0.00446%	22,445
Admixed American	0.0017%	58,846
Finnishnot grpmax-eligible	0.00161%	62,158

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.Ile16Thr
Coding: c.47T>C
MANE Select: NM_003965
Type: single nucleotide variant
Location: chr3:46408126 (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-ile16thr (accessed [today's date]).

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