Is ENG c.360+4A>G pathogenic?

ENG c.360+4A>G is classified Likely pathogenic in ENG (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-11-17). Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ENG c.360+4A>G?

ENG c.360+4A>G is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG c.360+4A>G in the general population?

ENG c.360+4A>G is very rare (popmax 0.000169%, nfe) (gnomAD).

ENG c.360+4A>G

rs1564457752 · VCV16671

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.78	donor loss · deltas
Pangolin	Δ0.66	loss · gain 0.34 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Non-coding constraint	Z 1.86	1 kb window · o/e 0.83 · regional · uncalibrated
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,948 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,702 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
Coding: c.360+4A>G
MANE Select: NM_001114753
dbSNP: rs1564457752
Type: single nucleotide variant
Location: chr9:127829683 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB

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.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
ENG p.Gly603Arg Likely pathogenic ★★★ same condition
ENG p.Leu221Pro Likely pathogenic ★★★ same condition
ENG p.Leu506His Likely 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-c-360-plus-4a-g (accessed [today's date]).

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