Is ERMARD p.Tyr221Ter (c.659_662dup) pathogenic?

ERMARD p.Tyr221Ter (c.659662dup) is classified Uncertain significance in ERMARD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). Very rare (popmax 8.47e-05%, nfe).

How common is ERMARD p.Tyr221Ter (c.659_662dup) in the general population?

ERMARD p.Tyr221Ter (c.659_662dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

ERMARD p.Tyr221Ter

c.659_662dup · rs1791310307 · VCV1690888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 0.23, phastCons 0.003

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,046 alleles

Overall 6.84e-05% 1/1,461,882 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: ERMARD
Protein: p.Tyr221Ter
Coding: c.659_662dup
MANE Select: NM_018341
dbSNP: rs1791310307
Type: Duplication
Location: chr6:169759889 (GRCh38)
Gene constraint: LOEUF 0.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.79

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

Similar variants

ERMARD p.Tyr221Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
ERMARD c.1854-5dup Likely benign ★★ same type
ERMARD p.Cys475_His476insProCys Uncertain significance ★ same type
ERMARD p.Leu459fs Conflicting classifications of pathogenicity ★ 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/ermard-p-tyr221ter (accessed [today's date]).

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