Is ENG p.Ile421Met (c.1263C>G) pathogenic?

ENG p.Ile421Met (c.1263C>G) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-26). AlphaMissense: ambiguous (0.3759); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ile421Met (c.1263C>G)?

ENG p.Ile421Met (c.1263C>G) is associated with Cardiovascular phenotype, telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ile421Met (c.1263C>G) in the general population?

ENG p.Ile421Met (c.1263C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ENG p.Ile421Met (c.1263C>G)?

AlphaMissense predicts ambiguous (score 0.3759) — an in-silico prediction, not a clinical call.

ENG p.Ile421Met

c.1263C>G · rs760446518 · VCV1514999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3759	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP -0.87, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.5	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 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000205% 3/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-American	0.00133%	75,056

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.Ile421Met
Coding: c.1263C>G
MANE Select: NM_001114753
dbSNP: rs760446518
Type: single nucleotide variant
Location: chr9:127819909 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 421: a β-strand; a disulfide bond; the zp domain

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.Ile421= 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
ENG p.Gly331Ser Pathogenic ★★★ ⚠ same condition
ENG p.Gly603Arg Likely pathogenic ★★★ same condition
ENG p.Leu221Pro 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-ile421met (accessed [today's date]).

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