Is ENG p.Leu325His (c.974T>A) pathogenic?

ENG p.Leu325His (c.974T>A) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-28). AlphaMissense: likely pathogenic (0.7636); Ultra-rare (popmax 0.077%, sas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Leu325His (c.974T>A)?

ENG p.Leu325His (c.974T>A) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Leu325His (c.974T>A) in the general population?

ENG p.Leu325His (c.974T>A) is ultra-rare (popmax 0.077%, 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.Leu325His (c.974T>A)?

AlphaMissense predicts likely pathogenic (score 0.7636) — an in-silico prediction, not a clinical call.

ENG p.Leu325His

c.974T>A · rs760001916 · VCV1981793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.077%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.7636	likely pathogenic
REVEL	0.387	indeterminate
SaProt	LLR -13.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.7	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 0.077% South Asian · 66/85,728 alleles

Filtering AF 0.062% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0566%

Overall 0.00418% 66/1,578,244 alleles · ultra-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.Leu325His
Coding: c.974T>A
MANE Select: NM_001114753
dbSNP: rs760001916
Type: single nucleotide variant
Location: chr9:127824817 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 325: a β-strand; a disulfide bond; 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

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.Leu325= Likely benign ★★ same residue
ENG p.Leu325fs Pathogenic ★ same residue
ENG p.Leu325Arg Likely pathogenic ★ same residue
ENG p.Leu325Phe 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

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-leu325his (accessed [today's date]).

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