Is ENG p.Cys53= (c.159C>T) pathogenic?

ENG p.Cys53= (c.159C>T) is classified Benign/Likely benign in ENG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.05%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Cys53= (c.159C>T)?

ENG p.Cys53= (c.159C>T) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Cys53= (c.159C>T) in the general population?

ENG p.Cys53= (c.159C>T) is low-frequency (popmax 1.05%, eas) (gnomAD).

ENG p.Cys53=

c.159C>T · rs148475405 · VCV237021

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4.5
Overall
CADD	1.058	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.05% East Asian · 472/44,882 alleles

Filtering AF 0.973% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.942%

Overall 0.0349% 563/1,614,236 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.05%	95
Remaining individualsnot grpmax-eligible	0.0608%	1,645
South Asian	0.0373%	2,679
Middle Eastern	0.0165%	6,060
Admixed American	0.015%	6,670
European (non-Finnish)	0.000763%	131,116

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.Cys53=
Coding: c.159C>T
MANE Select: NM_001114753
dbSNP: rs148475405
Type: single nucleotide variant
Location: chr9:127843154 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 53: a disulfide bond; a UniProt-annotated variant site (in hht1; impairs protein folding; abolishes expression at the cell surface); the 'required for interaction with gdf2' region; the 'or2' region; a β-strand

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: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Cys53Arg Pathogenic/Likely pathogenic ★★ same residue
ENG p.Cys53Ter Pathogenic ★★ same residue
ENG p.Cys53Ser Uncertain significance ★ ⚠ same residue
ENG p.Cys53Tyr Likely benign ★ ⚠ 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

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-cys53 (accessed [today's date]).

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