Is ENG p.Leu221Pro (c.662T>C) pathogenic?

ENG p.Leu221Pro (c.662T>C) is classified Likely pathogenic in ENG (ClinVar, Expert panel, 8 submitters; last evaluated 2024-03-15). AlphaMissense: likely pathogenic (0.9396); Absent from gnomAD v4.1; Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Leu221Pro (c.662T>C)?

ENG p.Leu221Pro (c.662T>C) is associated with telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Leu221Pro (c.662T>C) in the general population?

ENG p.Leu221Pro (c.662T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

What do computational predictors say about ENG p.Leu221Pro (c.662T>C)?

AlphaMissense predicts likely pathogenic (score 0.9396) — an in-silico prediction, not a clinical call.

ENG p.Leu221Pro

c.662T>C · rs1554810378 · VCV435060

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9396 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

telangiectasia, hereditary hemorrhagic, type 1

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

Likely Pathogenic for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):

PP4_Moderate PM2_Supporting PS3_Supporting PS4

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.662T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 221 (p.Leu221Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 10545596, 15880681, 17384219, 18498373, 20414677, 22991266, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The computational predictor REVEL gives a score of 0.478, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, protein expression assays in cell lines showed the variant causes reduced endoglin expression (PS3_Supporting; PMID: 10545596). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP4_Moderate, PS3_Supporting, PM2_Supporting (specification version 1.0.0; 1/4/2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9396	likely pathogenic ✓ concordant with ClinVar · top 3% in ENG
REVEL	0.478	indeterminate
SaProt	LLR -14.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
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	26.4	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.Leu221Pro
Coding: c.662T>C
MANE Select: NM_001114753
dbSNP: rs1554810378
Type: single nucleotide variant
Location: chr9:127825722 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 221: a β-strand; a UniProt-annotated variant site (in hht1; impairs protein folding; strongly reduces expression at the cell surface); 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

telangiectasia, hereditary hemorrhagic, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemorrhagic telangiectasia

For Hereditary hemorrhagic telangiectasia (Orphanet):

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

Similar variants

ENG p.Leu221= Likely benign ★★ same residue
ENG p.Leu221Arg Conflicting classifications of pathogenicity ★ ⚠ 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-leu221pro (accessed [today's date]).

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