Is ENG p.Pro75Leu (c.224C>T) pathogenic?

ENG p.Pro75Leu (c.224C>T) is classified Likely benign in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.005%, amr); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Pro75Leu (c.224C>T)?

ENG p.Pro75Leu (c.224C>T) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Pro75Leu (c.224C>T) in the general population?

ENG p.Pro75Leu (c.224C>T) is very rare (popmax 0.005%, amr) (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.Pro75Leu (c.224C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

ENG p.Pro75Leu

c.224C>T · VCV4782166

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP -0.45
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	2.593	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

Grpmax group 0.005% Admixed American · 3/59,978 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,993
European (non-Finnish)	0.000424%	236,004

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.Pro75Leu
Coding: c.224C>T
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127829823 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 75: a disulfide bond; the 'required for interaction with gdf2' region; the 'or2' region

Full ENG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hereditary hemorrhagic telangiectasia (Orphanet):

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

Similar variants

ENG p.Pro75Thr Uncertain significance ★★ ⚠ same residue
ENG p.Pro75= Benign/Likely benign ★★ same residue
ENG p.Pro75Ser Uncertain significance ★ ⚠ same residue
ENG p.Pro75fs 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

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-pro75leu (accessed [today's date]).

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