Is ENG p.Lys438= (c.1314A>G) pathogenic?

ENG p.Lys438= (c.1314A>G) is classified Uncertain significance in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). Ultra-rare (popmax 0.0332%, mid); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Lys438= (c.1314A>G)?

ENG p.Lys438= (c.1314A>G) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Lys438= (c.1314A>G) in the general population?

ENG p.Lys438= (c.1314A>G) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

ENG p.Lys438=

c.1314A>G · rs750412250 · VCV1489331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.92	acceptor gain · deltas
Pangolin	Δ0.75	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.1	GERP 1.6, phastCons 1
Overall
CADD	19.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,032 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000248% 4/1,613,950 alleles · ultra-rare exomes 4/1,461,682 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,016
East Asian	0.00446%	22,434

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.Lys438=
Coding: c.1314A>G
MANE Select: NM_001114753
dbSNP: rs750412250
Type: single nucleotide variant
Location: chr9:127818830 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 438: a β-strand; 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.Lys438Ter Pathogenic/Likely pathogenic ★★ same residue
ENG p.Lys438Arg Uncertain significance ★★ ⚠ 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-lys438 (accessed [today's date]).

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