Is ENG p.Thr538= (c.1614A>G) pathogenic?

ENG p.Thr538= (c.1614A>G) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-02). Very rare (popmax 6.84e-05%); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Thr538= (c.1614A>G)?

ENG p.Thr538= (c.1614A>G) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Thr538= (c.1614A>G) in the general population?

ENG p.Thr538= (c.1614A>G) is very rare (popmax 6.84e-05%) (gnomAD).

ENG p.Thr538=

c.1614A>G · rs1247391985 · VCV913035

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.63	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -0.59, phastCons 1
Overall
CADD	8.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,872 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.Thr538=
Coding: c.1614A>G
MANE Select: NM_001114753
dbSNP: rs1247391985
Type: single nucleotide variant
Location: chr9:127818192 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 538: a β-strand; a disulfide bond

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.Thr538Ala Conflicting classifications of pathogenicity ★ same residue
ENG p.Thr538Lys Uncertain significance ★ same residue
ENG p.Thr538fs Pathogenic ★★ 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

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-thr538 (accessed [today's date]).

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