Is DRG2 p.Phe228Leu (c.682T>C) pathogenic?

DRG2 p.Phe228Leu (c.682T>C) is classified Uncertain significance in DRG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.6532); Ultra-rare (popmax 0.0547%, afr).

How common is DRG2 p.Phe228Leu (c.682T>C) in the general population?

DRG2 p.Phe228Leu (c.682T>C) is ultra-rare (popmax 0.0547%, afr) (gnomAD).

What do computational predictors say about DRG2 p.Phe228Leu (c.682T>C)?

AlphaMissense predicts likely pathogenic (score 0.6532) — an in-silico prediction, not a clinical call.

DRG2 p.Phe228Leu

c.682T>C · VCV4244836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6532 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6532	likely pathogenic
REVEL	0.215	benign-leaning
SaProt	LLR -3.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	21.3	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 0.0547% African / African-American · 41/75,002 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.00279% 45/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0547%	1,829
Admixed American	0.00333%	30,008
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	8.47e-05%	1,179,999

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.Phe228Leu
Coding: c.682T>C
MANE Select: NM_001388
Type: single nucleotide variant
Location: chr17:18101543 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.40
Residue 228: 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-phe228leu (accessed [today's date]).

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