Is ENG p.Cys549Tyr (c.1646G>A) pathogenic?

ENG p.Cys549Tyr (c.1646G>A) is classified Pathogenic/Likely pathogenic in ENG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-16). AlphaMissense: likely pathogenic (0.9815); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Cys549Tyr (c.1646G>A)?

ENG p.Cys549Tyr (c.1646G>A) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Cys549Tyr (c.1646G>A) in the general population?

ENG p.Cys549Tyr (c.1646G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENG p.Cys549Tyr (c.1646G>A)?

AlphaMissense predicts likely pathogenic (score 0.9815) — an in-silico prediction, not a clinical call.

ENG p.Cys549Tyr

c.1646G>A · rs1060501421 · VCV407135

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9815 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9815	likely pathogenic ✓ concordant with ClinVar
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENG
Protein: p.Cys549Tyr
Coding: c.1646G>A
dbSNP: rs1060501421
Type: single nucleotide variant
Location: chr9:127818160 (GRCh38)

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

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-cys549tyr (accessed [today's date]).

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