Is ENG p.Ala60= (c.180C>A) pathogenic?

ENG p.Ala60= (c.180C>A) is classified Benign/Likely benign in ENG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-12). Rare (popmax 0.418%, afr); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Ala60= (c.180C>A)?

ENG p.Ala60= (c.180C>A) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ala60= (c.180C>A) in the general population?

ENG p.Ala60= (c.180C>A) is rare (popmax 0.418%, afr) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

ENG p.Ala60=

c.180C>A · rs146188464 · VCV727947

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.418%, afr)

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 -2.1	GERP -4.5
Overall
CADD	0.103	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.418% African / African-American · 314/75,056 alleles

Filtering AF 0.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.365%

Overall 0.0206% 332/1,614,244 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.418%	239
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.0117%	8,576
European (non-Finnish)	0.000169%	590,019

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.Ala60=
Coding: c.180C>A
MANE Select: NM_001114753
dbSNP: rs146188464
Type: single nucleotide variant
Location: chr9:127843133 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 60: a disulfide bond; the 'required for interaction with gdf2' region; the 'or2' 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.Ala60Asp Benign/Likely benign ★★ same residue
ENG p.Ala60Val Likely benign ★★ same residue
ENG p.Ala60Glu 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

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-ala60 (accessed [today's date]).

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