Is ENG p.Val236Met (c.706G>A) pathogenic?

ENG p.Val236Met (c.706G>A) is classified Likely pathogenic in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-10). AlphaMissense: likely benign (0.2936); Very rare (popmax 0.0055%, sas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Val236Met (c.706G>A)?

ENG p.Val236Met (c.706G>A) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val236Met (c.706G>A) in the general population?

ENG p.Val236Met (c.706G>A) is very rare (popmax 0.0055%, sas) (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.Val236Met (c.706G>A)?

AlphaMissense predicts likely benign (score 0.2936) — an in-silico prediction, not a clinical call.

ENG p.Val236Met

c.706G>A · rs754136153 · VCV1925043

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.2936	likely benign ⚠ discordant with ClinVar
REVEL	0.238	benign-leaning
SaProt	LLR -10.31	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 2.2	GERP -0.49, phastCons 0.97
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.6	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 0.0055% South Asian · 5/90,876 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000373% 6/1,610,266 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,175
European (non-Finnish)	8.48e-05%	1,179,542

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.Val236Met
Coding: c.706G>A
MANE Select: NM_001114753
dbSNP: rs754136153
Type: single nucleotide variant
Location: chr9:127825341 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 236: a β-strand; a UniProt-annotated variant site (in hht1; uncertain significance); 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.Val236= Likely benign ★★ same residue
ENG p.Val236Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Val236del Conflicting classifications of pathogenicity ★ same residue
ENG p.Val236Ala Uncertain significance ★ ⚠ same residue
ENG p.Val236Gly Uncertain significance ★ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr 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-val236met (accessed [today's date]).

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