Is CDR2L p.Arg74Gln (c.221G>A) pathogenic?

CDR2L p.Arg74Gln (c.221G>A) is classified Uncertain significance in CDR2L (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.2236); Ultra-rare (popmax 0.0545%, nfe).

How common is CDR2L p.Arg74Gln (c.221G>A) in the general population?

CDR2L p.Arg74Gln (c.221G>A) is ultra-rare (popmax 0.0545%, nfe) (gnomAD).

What do computational predictors say about CDR2L p.Arg74Gln (c.221G>A)?

AlphaMissense predicts likely benign (score 0.2236) — an in-silico prediction, not a clinical call.

CDR2L p.Arg74Gln

c.221G>A · rs371537062 · VCV2315172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2236 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0545%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2236	likely benign
REVEL	0.583	indeterminate
SaProt	LLR -9.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.037 · regional, not allelic
Overall
CADD	32.0	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 0.0545% European (non-Finnish) · 642/1,178,700 alleles

Filtering AF 0.051% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0496%

Overall 0.0418% 673/1,610,516 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0545%	1,836
Remaining individualsnot grpmax-eligible	0.0225%	4,453
Admixed American	0.00842%	11,870
African / African-American	0.00803%	12,461
Finnishnot grpmax-eligible	0.00628%	15,914
East Asian	0.00446%	22,414

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: CDR2L
Protein: p.Arg74Gln
Coding: c.221G>A
MANE Select: NM_014603
dbSNP: rs371537062
Type: single nucleotide variant
Location: chr17:75001369 (GRCh38)
Gene constraint: LOEUF 1.601 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.27

Full CDR2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDR2L p.Ala201Glu Uncertain significance ★ ⚠ same type
CDR2L p.Ala222Thr Uncertain significance ★ ⚠ same type
CDR2L p.Ala274Asp Uncertain significance ★ ⚠ same type
CDR2L p.Ala5Ser Uncertain significance ★ ⚠ same type
CDR2L p.Ala81Ser Uncertain significance ★ ⚠ same type
CDR2L p.Arg121His Uncertain significance ★ ⚠ same type
CDR2L p.Arg146Gln Uncertain significance ★ ⚠ same type
CDR2L p.Arg146Trp 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/cdr2l-p-arg74gln (accessed [today's date]).

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