Is DRG2 p.Cys223Ser (c.668G>C) pathogenic?

DRG2 p.Cys223Ser (c.668G>C) is classified Uncertain significance in DRG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.302); Very rare (popmax 0.005%, amr).

How common is DRG2 p.Cys223Ser (c.668G>C) in the general population?

DRG2 p.Cys223Ser (c.668G>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about DRG2 p.Cys223Ser (c.668G>C)?

AlphaMissense predicts likely benign (score 0.302) — an in-silico prediction, not a clinical call.

DRG2 p.Cys223Ser

c.668G>C · VCV4244832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.302	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -10.63	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	22.9	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 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,000
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: DRG2
Protein: p.Cys223Ser
Coding: c.668G>C
MANE Select: NM_001388
Type: single nucleotide variant
Location: chr17:18101529 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.40
Residue 223: the obg-type g domain

Full DRG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRG2 p.Ile359= Benign ★★ same type
DRG2 p.Ala135Ser Uncertain significance ★ ⚠ same type
DRG2 p.Ala137Val Uncertain significance ★ ⚠ same type
DRG2 p.Ala260Val Uncertain significance ★ same type
DRG2 p.Ala306Thr Uncertain significance ★ ⚠ same type
DRG2 p.Ala32Val Uncertain significance ★ ⚠ same type
DRG2 p.Ala35Thr Uncertain significance ★ ⚠ same type
DRG2 p.Ala63Val 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/drg2-p-cys223ser (accessed [today's date]).

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