Is ENG p.Arg406Cys (c.1216C>T) pathogenic?

ENG p.Arg406Cys (c.1216C>T) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.2333); Very rare (popmax 0.00223%, eas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Arg406Cys (c.1216C>T)?

ENG p.Arg406Cys (c.1216C>T) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Arg406Cys (c.1216C>T) in the general population?

ENG p.Arg406Cys (c.1216C>T) is very rare (popmax 0.00223%, eas) (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.Arg406Cys (c.1216C>T)?

AlphaMissense predicts likely benign (score 0.2333) — an in-silico prediction, not a clinical call.

ENG p.Arg406Cys

c.1216C>T · rs751787590 · VCV1415156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.2333	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -11.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.99, phastCons 0.02
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	20.7	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 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000496% 8/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,490
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)	0.000424%	236,011

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.Arg406Cys
Coding: c.1216C>T
MANE Select: NM_001114753
dbSNP: rs751787590
Type: single nucleotide variant
Location: chr9:127819956 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 406: 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

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.Arg406= Likely benign ★★ same residue
ENG p.Arg406Gly Conflicting classifications of pathogenicity ★ ⚠ 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-arg406cys (accessed [today's date]).

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