Is ENG p.Arg205Trp (c.613C>T) pathogenic?

ENG p.Arg205Trp (c.613C>T) is classified Likely benign in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.0973); Very rare (popmax 0.00452%, eas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Arg205Trp (c.613C>T)?

ENG p.Arg205Trp (c.613C>T) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Arg205Trp (c.613C>T) in the general population?

ENG p.Arg205Trp (c.613C>T) is very rare (popmax 0.00452%, 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.Arg205Trp (c.613C>T)?

AlphaMissense predicts likely benign (score 0.0973) — an in-silico prediction, not a clinical call.

ENG p.Arg205Trp

c.613C>T · rs762209698 · VCV1001608

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00452%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.0973	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -8.17	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 1.5	GERP -0.58, phastCons 0.92
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	20.1	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 0.00452% East Asian · 2/44,220 alleles

Filtering AF 0.00075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000541%

Overall 0.00119% 19/1,598,336 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00452%	22,110
Admixed American	0.00172%	58,254
Remaining individualsnot grpmax-eligible	0.00162%	61,778
European (non-Finnish)	0.00119%	83,867
South Asian	0.00113%	88,804

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.Arg205Trp
Coding: c.613C>T
MANE Select: NM_001114753
dbSNP: rs762209698
Type: single nucleotide variant
Location: chr9:127825771 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 205: a β-strand; a disulfide bond; a UniProt-annotated variant site (sequence variant); 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.Arg205Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Arg205= Likely benign ★ same residue
ENG p.Arg205Gln Likely benign ★ same residue
ENG p.Arg205fs Pathogenic ★ 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-arg205trp (accessed [today's date]).

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