Is ENG p.Pro131Leu (c.392C>T) pathogenic?

ENG p.Pro131Leu (c.392C>T) is classified Benign in ENG (ClinVar, Expert panel, 12 submitters; last evaluated 2024-03-15). AlphaMissense: likely benign (0.0735); Low-frequency (popmax 2.54%, sas); Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Pro131Leu (c.392C>T)?

ENG p.Pro131Leu (c.392C>T) is associated with telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia, Galloway-Mowat syndrome 1 (ClinVar).

How common is ENG p.Pro131Leu (c.392C>T) in the general population?

ENG p.Pro131Leu (c.392C>T) is low-frequency (popmax 2.54%, sas) (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.Pro131Leu (c.392C>T)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

ENG p.Pro131Leu

c.392C>T · rs139398993 · VCV161232

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.54%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

telangiectasia, hereditary hemorrhagic, type 1

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

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

BA1

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign 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: BA1 (specification version 1.0.0; 1/4/2024).

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

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.25	GERP -4.1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	2.835	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 2.54% South Asian · 2,313/91,068 alleles

Filtering AF 2.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.42%

Overall 0.267% 4,305/1,613,834 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.54%	39
Ashkenazi Jewishnot grpmax-eligible	1.28%	78
Middle Eastern	0.799%	125
Remaining individualsnot grpmax-eligible	0.414%	241
Admixed American	0.135%	741
European (non-Finnish)	0.101%	991
African / African-American	0.024%	4,167
Finnishnot grpmax-eligible	0.0219%	4,564
East Asian	0.00223%	44,878

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.Pro131Leu
Coding: c.392C>T
MANE Select: NM_001114753
dbSNP: rs139398993
Type: single nucleotide variant
Location: chr9:127826641 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 131: 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

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

Also linked: hereditary hemorrhagic telangiectasia Galloway-Mowat syndrome 1

For Hereditary hemorrhagic telangiectasia (Orphanet):

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

Similar variants

ENG p.Pro131Gln Likely benign ★ ⚠ same residue
ENG p.Pro131fs Pathogenic ★★ same residue
ENG p.Pro131Ala Uncertain significance ★ ⚠ same residue
ENG p.Pro131= Likely benign ★ 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-pro131leu (accessed [today's date]).

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