Is ENG p.Pro75= (c.225G>A) pathogenic?

ENG p.Pro75= (c.225G>A) is classified Benign/Likely benign in ENG (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). Rare (popmax 0.281%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Pro75= (c.225G>A)?

ENG p.Pro75= (c.225G>A) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Pro75= (c.225G>A) in the general population?

ENG p.Pro75= (c.225G>A) is rare (popmax 0.281%, afr) (gnomAD).

ENG p.Pro75=

c.225G>A · rs116146060 · VCV414305

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.281%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.2
Overall
CADD	10.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.281% African / African-American · 211/75,020 alleles

Filtering AF 0.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.238%

Overall 0.0207% 334/1,613,968 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.281%	356
Remaining individualsnot grpmax-eligible	0.0464%	2,155
East Asian	0.0267%	3,740
Admixed American	0.02%	5,001
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00542%	18,438
South Asian	0.00439%	22,769
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Pro75=
Coding: c.225G>A
MANE Select: NM_001114753
dbSNP: rs116146060
Type: single nucleotide variant
Location: chr9:127829822 (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

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.Pro75Thr Uncertain significance ★★ ⚠ same residue
ENG p.Pro75Ser Uncertain significance ★ ⚠ same residue
ENG p.Pro75Leu Likely benign ★ ⚠ 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-pro75 (accessed [today's date]).

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