Is DRG2 p.Glu216Val (c.647A>T) pathogenic?

DRG2 p.Glu216Val (c.647A>T) is classified Uncertain significance in DRG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9693); Absent from gnomAD v4.1.

How common is DRG2 p.Glu216Val (c.647A>T) in the general population?

DRG2 p.Glu216Val (c.647A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DRG2 p.Glu216Val (c.647A>T)?

AlphaMissense predicts likely pathogenic (score 0.9693) — an in-silico prediction, not a clinical call.

DRG2 p.Glu216Val

c.647A>T · VCV4662170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9693 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9693	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -14.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.31	acceptor loss, 15 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DRG2
Protein: p.Glu216Val
Coding: c.647A>T
MANE Select: NM_001388
Type: single nucleotide variant
Location: chr17:18101508 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.40
Residue 216: 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-glu216val (accessed [today's date]).

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