Is ENG p.Leu203Phe (c.609G>C) pathogenic?

ENG p.Leu203Phe (c.609G>C) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-30). AlphaMissense: likely benign (0.0886); Ultra-rare (popmax 0.0137%, amr); Associated with ENG-related disorder.

What condition is associated with ENG p.Leu203Phe (c.609G>C)?

ENG p.Leu203Phe (c.609G>C) is associated with ENG-related disorder, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Leu203Phe (c.609G>C) in the general population?

ENG p.Leu203Phe (c.609G>C) is ultra-rare (popmax 0.0137%, amr) (gnomAD).

What do computational predictors say about ENG p.Leu203Phe (c.609G>C)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

ENG p.Leu203Phe

c.609G>C · rs767850408 · VCV1513279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ENG-related disorder

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.74	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 -3.4	GERP -3.6
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	1.625	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 0.0137% Admixed American · 8/58,188 alleles

Filtering AF 0.00679% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00495%

Overall 0.000622% 9/1,446,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0137%	7,274
South Asian	0.00113%	88,780

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.Leu203Phe
Coding: c.609G>C
MANE Select: NM_001114753
dbSNP: rs767850408
Type: single nucleotide variant
Location: chr9:127825775 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 203: 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

ENG-related disorder

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

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
ENG p.Leu221Pro Likely pathogenic ★★★ same condition
ENG p.Leu506His 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-leu203phe (accessed [today's date]).

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