Is CDR2 p.Arg308Cys (c.922C>T) pathogenic?

CDR2 p.Arg308Cys (c.922C>T) is classified Uncertain significance in CDR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.2324); Ultra-rare (popmax 0.0121%, sas).

How common is CDR2 p.Arg308Cys (c.922C>T) in the general population?

CDR2 p.Arg308Cys (c.922C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about CDR2 p.Arg308Cys (c.922C>T)?

AlphaMissense predicts likely benign (score 0.2324) — an in-silico prediction, not a clinical call.

CDR2 p.Arg308Cys

c.922C>T · rs372706388 · VCV2399584

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2324 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2324	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -8.93	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 12	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 27 kb · p 0.028 · regional, not allelic
Overall
CADD	29.1	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 0.0121% South Asian · 11/91,074 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00774% 125/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
European (non-Finnish)	0.00932%	10,727
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,890
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Arg308Cys
Coding: c.922C>T
MANE Select: NM_001802
dbSNP: rs372706388
Type: single nucleotide variant
Location: chr16:22347408 (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.Arg308Leu Uncertain significance ★ ⚠ same residue
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

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-arg308cys (accessed [today's date]).

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