Is ENG p.Lys374Ser (c.1121_1122delinsGC) pathogenic?

ENG p.Lys374Ser (c.11211122delinsGC) is classified Pathogenic/Likely pathogenic in ENG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-12). No gnomAD frequency available for this variant; Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Lys374Ser (c.1121_1122delinsGC)?

ENG p.Lys374Ser (c.1121_1122delinsGC) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Lys374Ser (c.1121_1122delinsGC) in the general population?

ENG p.Lys374Ser (c.1121_1122delinsGC) is no gnomAD frequency available for this variant (gnomAD).

ENG p.Lys374Ser

c.1121_1122delinsGC · rs2131885751 · VCV1701581

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.1	GERP -1.5, phastCons 0.013
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ENG
Protein: p.Lys374Ser
Coding: c.1121_1122delinsGC
MANE Select: NM_001114753
dbSNP: rs2131885751
Type: Indel
Location: chr9:127824316 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 374: an α-helix; the zp domain; a UniProt-annotated variant site (in hht1; uncertain significance)

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 hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Lys374fs Pathogenic ★ same residue
ENG p.Lys374Glu Likely pathogenic ★ same residue
ENG p.Lys374= Likely benign ★ same residue
ENG p.Ser328Ter Pathogenic ★★ same condition
ENG p.Thr344fs Pathogenic ★★ same condition
ENG p.Ala60Glu Benign/Likely benign ★★ same condition
ENG c.1135-3_1135-2delinsAG Likely pathogenic ★ same condition
ENG p.Ala151fs 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-lys374ser (accessed [today's date]).

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