Is ENG p.Glu195Ter (c.583G>T) pathogenic?

ENG p.Glu195Ter (c.583G>T) is classified Likely pathogenic in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). Absent from gnomAD v4.1.

How common is ENG p.Glu195Ter (c.583G>T) in the general population?

ENG p.Glu195Ter (c.583G>T) is absent from gnomAD v4.1 (gnomAD).

ENG p.Glu195Ter

c.583G>T · VCV4526377

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 5 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP 1.9, phastCons 0.039
Overall
CADD	33.0	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

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: ENG
Protein: p.Glu195Ter
Coding: c.583G>T
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127825801 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 195: a β-strand; a disulfide bond; a UniProt-annotated variant site (in hht1); the 'required for interaction with gdf2' region; the 'or2' region

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

Similar variants

ENG p.Glu195Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Glu195Lys Uncertain significance ★ ⚠ same residue
ENG p.Glu195= Likely benign ★ same residue
ENG p.Glu195Gln Likely benign ★ same residue
ENG p.Glu195fs Pathogenic ★★ same residue
ENG p.Glu195del Uncertain significance ★ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same type
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ 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/eng-p-glu195ter (accessed [today's date]).

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