Is ENG p.Val212= (c.636G>C) pathogenic?

ENG p.Val212= (c.636G>C) is classified Likely benign in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-04). Very rare (popmax 0.00902%, eas); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Val212= (c.636G>C)?

ENG p.Val212= (c.636G>C) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val212= (c.636G>C) in the general population?

ENG p.Val212= (c.636G>C) is very rare (popmax 0.00902%, eas) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

ENG p.Val212=

c.636G>C · rs759493966 · VCV1590300

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00902%, eas)

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP 0.79, phastCons 0.004
Overall
CADD	6.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00902% East Asian · 4/44,348 alleles

Filtering AF 0.003% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00182%

Overall 0.00025% 4/1,600,014 alleles · very rare exomes 3/1,447,924 · genomes 1/152,090 · joint denominator

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.Val212=
Coding: c.636G>C
MANE Select: NM_001114753
dbSNP: rs759493966
Type: single nucleotide variant
Location: chr9:127825748 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 212: 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.Val212Met Benign ★★ same residue
ENG p.Val212fs 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
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-val212 (accessed [today's date]).

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