Is ENG p.Ala175Ser (c.523G>T) pathogenic?

ENG p.Ala175Ser (c.523G>T) is classified Pathogenic/Likely pathogenic in ENG (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0774); Absent from gnomAD v4.1; Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Ala175Ser (c.523G>T)?

ENG p.Ala175Ser (c.523G>T) is associated with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 1 (ClinVar).

How common is ENG p.Ala175Ser (c.523G>T) in the general population?

ENG p.Ala175Ser (c.523G>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

What do computational predictors say about ENG p.Ala175Ser (c.523G>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

ENG p.Ala175Ser

c.523G>T · rs1588583488 · VCV641795

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign ⚠ discordant with ClinVar
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.91	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.71	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ala175Ser
Coding: c.523G>T
MANE Select: NM_001114753
dbSNP: rs1588583488
Type: single nucleotide variant
Location: chr9:127826510 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 175: a disulfide bond; 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

hereditary hemorrhagic telangiectasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: telangiectasia, hereditary hemorrhagic, type 1

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Ala175Pro Pathogenic ★★ ⚠ same residue
ENG p.Ala175Thr Pathogenic ★★ ⚠ same residue
ENG p.Ala175= 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-ala175ser (accessed [today's date]).

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