Is ENG p.Ser449fs (c.1346_1347del) pathogenic?

ENG p.Ser449fs (c.13461347del) is classified Pathogenic in ENG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-08-08). Very rare (popmax 8.47e-05%, nfe); Associated with ENG-related disorder.

What condition is associated with ENG p.Ser449fs (c.1346_1347del)?

ENG p.Ser449fs (c.1346_1347del) is associated with ENG-related disorder, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ser449fs (c.1346_1347del) in the general population?

ENG p.Ser449fs (c.1346_1347del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

ENG p.Ser449fs

c.1346_1347del · rs1564453019 · VCV572526

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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

Conditions

ENG-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.17	GERP -3.1, phastCons 0.008

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) · 1/1,180,002 alleles

Overall 6.84e-05% 1/1,461,828 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.Ser449fs
Coding: c.1346_1347del
MANE Select: NM_001114753
dbSNP: rs1564453019
Type: Microsatellite
Location: chr9:127818797 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 449: a β-strand; the zp domain

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

Disease context

ENG-related disorder

Also linked: telangiectasia, hereditary hemorrhagic, type 1 hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Arg153fs Pathogenic/Likely pathogenic ★★ same condition
ENG p.Arg478fs Pathogenic ★★ same condition
ENG p.Gly214fs Pathogenic ★★ same condition
ENG p.Pro296fs Pathogenic/Likely pathogenic ★★ same condition
ENG p.Thr200fs Pathogenic ★★ same condition
ENG p.Thr45fs Pathogenic ★★ same condition
ENG p.Thr538fs Pathogenic ★★ same condition
ENG p.Val517fs 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-ser449fs (accessed [today's date]).

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