Is ENG p.Ile220Thr (c.659T>C) pathogenic?

ENG p.Ile220Thr (c.659T>C) is classified Pathogenic/Likely pathogenic in ENG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.9674); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ile220Thr (c.659T>C)?

ENG p.Ile220Thr (c.659T>C) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ile220Thr (c.659T>C) in the general population?

ENG p.Ile220Thr (c.659T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENG p.Ile220Thr (c.659T>C)?

AlphaMissense predicts likely pathogenic (score 0.9674) — an in-silico prediction, not a clinical call.

ENG p.Ile220Thr

c.659T>C · rs1588582695 · VCV651770

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9674 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,596,302)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9674	likely pathogenic ✓ concordant with ClinVar · top 2% in ENG
REVEL	0.399	indeterminate
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.8	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

No allele count reported in gnomAD v4.1 (AN 1,596,302). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ENG
Protein: p.Ile220Thr
Coding: c.659T>C
MANE Select: NM_001114753
dbSNP: rs1588582695
Type: single nucleotide variant
Location: chr9:127825725 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 220: a β-strand; a UniProt-annotated variant site (in hht1); the 'required for interaction with gdf2' region; the 'or1, c-terminal part' region

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.Ile220= Likely benign ★★ same residue
ENG p.Ile220fs Pathogenic ★ same residue
ENG p.Ile220Asn 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

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-ile220thr (accessed [today's date]).

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