Is ENG p.Ala591= (c.1773C>T) pathogenic?

ENG p.Ala591= (c.1773C>T) is classified Likely benign in ENG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-01). Very rare (popmax 0.00221%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ala591= (c.1773C>T)?

ENG p.Ala591= (c.1773C>T) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ala591= (c.1773C>T) in the general population?

ENG p.Ala591= (c.1773C>T) is very rare (popmax 0.00221%, sas) (gnomAD).

ENG p.Ala591=

c.1773C>T · rs766073909 · VCV2965041

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.9	GERP -3.5
Overall
CADD	2.006	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,462 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000869% 14/1,610,720 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,231
Remaining individualsnot grpmax-eligible	0.0016%	62,312
European (non-Finnish)	0.000933%	107,198

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.Ala591=
Coding: c.1773C>T
MANE Select: NM_001114753
dbSNP: rs766073909
Type: single nucleotide variant
Location: chr9:127816022 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Ala591Thr Benign/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-ala591 (accessed [today's date]).

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