Is ENG p.Arg93Ter (c.277C>T) pathogenic?

ENG p.Arg93Ter (c.277C>T) is classified Pathogenic in ENG (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-19). Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Arg93Ter (c.277C>T)?

ENG p.Arg93Ter (c.277C>T) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, pulmonary arterial hypertension (ClinVar).

How common is ENG p.Arg93Ter (c.277C>T) in the general population?

ENG p.Arg93Ter (c.277C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

ENG p.Arg93Ter

c.277C>T · rs886039506 · VCV265371

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Cardiovascular phenotype

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 in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.6, phastCons 0.99
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,022 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,856 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: ENG
Protein: p.Arg93Ter
Coding: c.277C>T
MANE Select: NM_001114753
dbSNP: rs886039506
Type: single nucleotide variant
Location: chr9:127829770 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 93: a disulfide bond; the 'required for interaction with gdf2' region; the 'or2' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: telangiectasia, hereditary hemorrhagic, type 1 pulmonary arterial hypertension hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Arg93Gly Uncertain significance ★ ⚠ same residue
ENG p.Arg93Gln Benign ★ same residue
ENG p.Arg93fs Pathogenic ★ same residue
ENG p.Arg529His Pathogenic ★★★ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr Pathogenic ★★★ same condition
ENG p.Cys549Gly Likely pathogenic ★★★ same condition
ENG p.Gly331Ser Pathogenic ★★★ ⚠ same condition

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/eng-p-arg93ter (accessed [today's date]).

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