Is ENG p.Val125Ala (c.374T>C) pathogenic?

ENG p.Val125Ala (c.374T>C) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.4541); Very rare (popmax 0.00356%, nfe); Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Val125Ala (c.374T>C)?

ENG p.Val125Ala (c.374T>C) is associated with telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val125Ala (c.374T>C) in the general population?

ENG p.Val125Ala (c.374T>C) is very rare (popmax 0.00356%, nfe) (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.Val125Ala (c.374T>C)?

AlphaMissense predicts ambiguous (score 0.4541) — an in-silico prediction, not a clinical call.

ENG p.Val125Ala

c.374T>C · rs750115837 · VCV402828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

telangiectasia, hereditary hemorrhagic, type 1

Computational evidence

Protein change
AlphaMissense	0.4541	ambiguous
REVEL	0.132	moderately benign-leaning
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 2, phastCons 0.99
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	15.72	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 0.00356% European (non-Finnish) · 42/1,179,946 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0026% 42/1,613,526 alleles · very rare

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.Val125Ala
Coding: c.374T>C
MANE Select: NM_001114753
dbSNP: rs750115837
Type: single nucleotide variant
Location: chr9:127826659 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 125: a β-strand; 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

For Hereditary hemorrhagic telangiectasia (Orphanet):

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

Similar variants

ENG p.Val125Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Val125Leu Uncertain significance ★ ⚠ 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-val125ala (accessed [today's date]).

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