Is ACVRL1 p.Ile245Val (c.733A>G) pathogenic?

ACVRL1 p.Ile245Val (c.733A>G) is classified Uncertain significance in ACVRL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-10). AlphaMissense: ambiguous (0.4827); Absent from gnomAD v4.1; Associated with telangiectasia, hereditary hemorrhagic, type 2.

What condition is associated with ACVRL1 p.Ile245Val (c.733A>G)?

ACVRL1 p.Ile245Val (c.733A>G) is associated with telangiectasia, hereditary hemorrhagic, type 2 (ClinVar).

How common is ACVRL1 p.Ile245Val (c.733A>G) in the general population?

ACVRL1 p.Ile245Val (c.733A>G) 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 ACVRL1 p.Ile245Val (c.733A>G)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

ACVRL1 p.Ile245Val

c.733A>G · VCV4082334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

telangiectasia, hereditary hemorrhagic, type 2

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.301	indeterminate
SaProt	LLR -9.54	tolerated
Splicing
SpliceAI	Δ0.86	donor gain · deltas
Pangolin	Δ0.46	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 7,154 bp · p 6.9e-20 · regional, not allelic
Overall
CADD	34.0	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: ACVRL1
Protein: p.Ile245Val
Coding: c.733A>G
MANE Select: NM_000020
Type: single nucleotide variant
Location: chr12:51914546 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.51 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.77 · 7 PDB
Residue 245: an α-helix; the protein kinase domain; a UniProt-annotated variant site (in); a UniProt-annotated variant site (in hht2; no loss of receptor activity in response to bmp9; mutant protein is capable of targeting the cell surface appropriately; affects splicing by inducing the creation of a new donor splice site and the loss of the 3' end of exon 6)

Full ACVRL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

telangiectasia, hereditary hemorrhagic, type 2 — 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

ACVRL1 p.Arg411Gln Pathogenic ★★★ same condition
ACVRL1 p.Asn98Ser Likely pathogenic ★★★ ⚠ same condition
ACVRL1 p.Cys46Ser Likely pathogenic ★★★ same condition
ACVRL1 p.Cys51Gly Likely pathogenic ★★★ same condition
ACVRL1 p.Cys89Phe Likely pathogenic ★★★ same condition
ACVRL1 p.Gln490Ter Pathogenic ★★★ same condition
ACVRL1 p.Glu236Lys Pathogenic ★★★ same condition
ACVRL1 p.His328Tyr 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/acvrl1-p-ile245val (accessed [today's date]).

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