Is ERG p.Gly226Val (c.677G>T) pathogenic?

ERG p.Gly226Val (c.677G>T) is classified Uncertain significance in ERG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.0011%, sas).

How common is ERG p.Gly226Val (c.677G>T) in the general population?

ERG p.Gly226Val (c.677G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ERG p.Gly226Val (c.677G>T)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

ERG p.Gly226Val

c.677G>T · rs1988444402 · VCV2543007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -7.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 19 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.4	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 0.0011% South Asian · 1/90,712 alleles

Overall 6.9e-05% 1/1,449,028 alleles · very rare

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: ERG
Protein: p.Gly226Val
Coding: c.677G>T
MANE Select: NM_182918
dbSNP: rs1988444402
Type: single nucleotide variant
Location: chr21:38400642 (GRCh38)
Gene constraint: LOEUF 0.234 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.25 · 8 PDB

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

Similar variants

ERG p.Asp363Gly Uncertain significance ★★ ⚠ same type
ERG c.389-2A>G Uncertain significance ★ same type
ERG c.40-56923A>G Uncertain significance ★ same type
ERG c.674-1G>A Uncertain significance ★ same type
ERG p.Ala368Thr Uncertain significance ★ ⚠ same type
ERG p.Ala387Pro Uncertain significance ★ ⚠ same type
ERG p.Ala88Asp Uncertain significance ★ ⚠ same type
ERG p.Arg178Gly 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/erg-p-gly226val (accessed [today's date]).

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