Is ENG p.Val504= (c.1512G>A) pathogenic?

ENG p.Val504= (c.1512G>A) is classified Likely benign in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-16). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Val504= (c.1512G>A)?

ENG p.Val504= (c.1512G>A) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val504= (c.1512G>A) in the general population?

ENG p.Val504= (c.1512G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

ENG p.Val504=

c.1512G>A · rs2131875976 · VCV1160520

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

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

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.54	GERP 0.55, phastCons 1
Overall
CADD	8.202	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.84e-05% 1/1,461,802 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.Val504=
Coding: c.1512G>A
MANE Select: NM_001114753
dbSNP: rs2131875976
Type: single nucleotide variant
Location: chr9:127818294 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 504: a β-strand; a disulfide bond; the zp domain; a UniProt-annotated variant site (in hht1; likely benign)

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

Disease context

hereditary hemorrhagic telangiectasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Val504Met Likely benign ★★★ same residue
ENG p.Val504Glu Uncertain significance ★ ⚠ 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
ENG p.Gly603Arg 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-p-val504 (accessed [today's date]).

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