Is ACVR1 p.Pro465Leu (c.1394C>T) pathogenic?

ACVR1 p.Pro465Leu (c.1394C>T) is classified Conflicting classifications of pathogenicity in ACVR1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.1032); Ultra-rare (popmax 0.0253%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACVR1 p.Pro465Leu (c.1394C>T)?

ACVR1 p.Pro465Leu (c.1394C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACVR1 p.Pro465Leu (c.1394C>T) in the general population?

ACVR1 p.Pro465Leu (c.1394C>T) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about ACVR1 p.Pro465Leu (c.1394C>T)?

AlphaMissense predicts likely benign (score 0.1032) — an in-silico prediction, not a clinical call.

ACVR1 p.Pro465Leu

c.1394C>T · rs750457181 · VCV2146537

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1032 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1032	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 0.003 · 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

Grpmax group 0.0253% South Asian · 23/91,082 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00459% 74/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,960
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,926
European (non-Finnish)	0.00347%	28,779
African / African-American	0.00267%	37,460

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: ACVR1
Protein: p.Pro465Leu
Coding: c.1394C>T
MANE Select: NM_001111067
dbSNP: rs750457181
Type: single nucleotide variant
Location: chr2:157738441 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 465: the protein kinase domain; an α-helix

Full ACVR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACVR1 p.Pro465= Conflicting classifications of pathogenicity ★ same residue
ACVR1 p.Pro465Ser Uncertain significance ★ ⚠ same residue
ACVR1 p.Gly328Glu Pathogenic/Likely pathogenic ★★ same condition
ACVR1 p.Arg147Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Arg307Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Arg417Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Gly39Val Uncertain significance ★★ ⚠ same condition
ACVR1 p.His121Tyr Uncertain significance ★★ ⚠ 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/acvr1-p-pro465leu (accessed [today's date]).

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