Is ENG p.Pro225Leu (c.674C>T) pathogenic?

ENG p.Pro225Leu (c.674C>T) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.1996); Very rare (popmax 0.00514%, amr); Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Pro225Leu (c.674C>T)?

ENG p.Pro225Leu (c.674C>T) is associated with telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Pro225Leu (c.674C>T) in the general population?

ENG p.Pro225Leu (c.674C>T) is very rare (popmax 0.00514%, 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.Pro225Leu (c.674C>T)?

AlphaMissense predicts likely benign (score 0.1996) — an in-silico prediction, not a clinical call.

ENG p.Pro225Leu

c.674C>T · rs781715616 · VCV864140

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00514%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

telangiectasia, hereditary hemorrhagic, type 1

Computational evidence

Protein change
AlphaMissense	0.1996	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -9.23	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 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00514% Admixed American · 3/58,416 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000678%

Overall 0.00139% 22/1,586,376 alleles · very rare exomes 18/1,434,612 · genomes 4/151,764 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00514%	19,472
South Asian	0.00339%	29,513
Finnishnot grpmax-eligible	0.00179%	55,752
African / African-American	0.00134%	74,450
European (non-Finnish)	0.0012%	83,547

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.Pro225Leu
Coding: c.674C>T
MANE Select: NM_001114753
dbSNP: rs781715616
Type: single nucleotide variant
Location: chr9:127825710 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 225: 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.Pro225Thr Uncertain significance ★★ ⚠ same residue
ENG p.Pro225= Benign/Likely benign ★★ same residue
ENG p.Pro225Ala Uncertain significance ★ ⚠ same residue
ENG p.Pro225Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Pro225Ser Uncertain significance ★ ⚠ same residue
ENG p.Pro225Arg Likely benign ★ same residue
ENG p.Pro225fs Pathogenic ★★ same residue
ENG p.Arg529His 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-pro225leu (accessed [today's date]).

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