Is ENG p.Thr617Met (c.1850C>T) pathogenic?

ENG p.Thr617Met (c.1850C>T) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-22). AlphaMissense: ambiguous (0.3462); Very rare (popmax 0.00875%, amr); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Thr617Met (c.1850C>T)?

ENG p.Thr617Met (c.1850C>T) is associated with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 1 (ClinVar).

How common is ENG p.Thr617Met (c.1850C>T) in the general population?

ENG p.Thr617Met (c.1850C>T) is very rare (popmax 0.00875%, amr) (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.Thr617Met (c.1850C>T)?

AlphaMissense predicts ambiguous (score 0.3462) — an in-silico prediction, not a clinical call.

ENG p.Thr617Met

c.1850C>T · rs201031046 · VCV810423

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3462 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00875%, amr)

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.3462	ambiguous
REVEL	0.639	indeterminate
SaProt	LLR -8.43	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00875% Admixed American · 5/57,158 alleles

Filtering AF 0.00339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00288%

Overall 0.00363% 58/1,596,604 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00875%	11,432
East Asian	0.00452%	22,124
European (non-Finnish)	0.00418%	23,923
Remaining individualsnot grpmax-eligible	0.00162%	61,844
South Asian	0.00113%	88,286

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.Thr617Met
Coding: c.1850C>T
MANE Select: NM_001114753
dbSNP: rs201031046
Type: single nucleotide variant
Location: chr9:127815945 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB

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

Also linked: telangiectasia, hereditary hemorrhagic, type 1

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Thr617= 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-thr617met (accessed [today's date]).

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