Is ENG p.Ala175= (c.525C>T) pathogenic?

ENG p.Ala175= (c.525C>T) is classified Likely benign in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-24). Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ala175= (c.525C>T)?

ENG p.Ala175= (c.525C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is ENG p.Ala175= (c.525C>T) in the general population?

ENG p.Ala175= (c.525C>T) is absent from gnomAD v4.1 (gnomAD).

ENG p.Ala175=

c.525C>T · rs1588583011 · VCV733699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.5	GERP -0.5, phastCons 0.92
Overall
CADD	8.043	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENG
Protein: p.Ala175=
Coding: c.525C>T
MANE Select: NM_001114753
dbSNP: rs1588583011
Type: single nucleotide variant
Location: chr9:127825859 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 175: a UniProt-annotated variant site (in hht1); 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

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

Similar variants

ENG p.Ala175Pro Pathogenic ★★ ⚠ same residue
ENG p.Ala175Thr Pathogenic ★★ ⚠ same residue
ENG p.Ala175Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
ENG c.1134+1G>T Pathogenic/Likely pathogenic ★★ same condition
ENG c.1311+2T>A Pathogenic ★★ same condition
ENG c.1428+1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.1687-1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.219+1G>A 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-ala175 (accessed [today's date]).

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