Is CDR2 p.Glu196Lys (c.586G>A) pathogenic?

CDR2 p.Glu196Lys (c.586G>A) is classified Uncertain significance in CDR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.07); Very rare (popmax 8.47e-05%, nfe).

How common is CDR2 p.Glu196Lys (c.586G>A) in the general population?

CDR2 p.Glu196Lys (c.586G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDR2 p.Glu196Lys (c.586G>A)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

CDR2 p.Glu196Lys

c.586G>A · VCV4651657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.79	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 2.3	phastCons 0.88
Regional constraint	o/e 0.91	unconstrained · MANE · 27 kb · p 0.028 · regional, not allelic
Overall
CADD	17.17	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,860 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: CDR2
Protein: p.Glu196Lys
Coding: c.586G>A
MANE Select: NM_001802
Type: single nucleotide variant
Location: chr16:22347744 (GRCh38)
Gene constraint: LOEUF 0.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.84

Full CDR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDR2 p.Ala107Val Uncertain significance ★ ⚠ same type
CDR2 p.Ala155Thr Uncertain significance ★ ⚠ same type
CDR2 p.Ala178Thr Uncertain significance ★ ⚠ same type
CDR2 p.Ala252Pro Uncertain significance ★ ⚠ same type
CDR2 p.Ala319Ser Uncertain significance ★ ⚠ same type
CDR2 p.Ala355Thr Uncertain significance ★ ⚠ same type
CDR2 p.Ala394Thr Uncertain significance ★ ⚠ same type
CDR2 p.Arg213Gln 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/cdr2-p-glu196lys (accessed [today's date]).

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