Is ACVR2B p.Leu8Phe (c.22C>T) pathogenic?

ACVR2B p.Leu8Phe (c.22C>T) is classified Uncertain significance in ACVR2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-19). AlphaMissense: likely benign (0.0528); Very rare (popmax 0.00626%, eas); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Leu8Phe (c.22C>T)?

ACVR2B p.Leu8Phe (c.22C>T) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Leu8Phe (c.22C>T) in the general population?

ACVR2B p.Leu8Phe (c.22C>T) is very rare (popmax 0.00626%, eas) (gnomAD).

What do computational predictors say about ACVR2B p.Leu8Phe (c.22C>T)?

AlphaMissense predicts likely benign (score 0.0528) — an in-silico prediction, not a clinical call.

ACVR2B p.Leu8Phe

c.22C>T · rs1470129412 · VCV2190827

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00626%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.0528	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP -0.006, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 23 kb · p 0.65 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00626% East Asian · 2/31,958 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000697%

Overall 0.00139% 18/1,297,606 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00626%	15,979
Remaining individualsnot grpmax-eligible	0.00208%	48,026
European (non-Finnish)	0.00147%	68,250

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: ACVR2B
Protein: p.Leu8Phe
Coding: c.22C>T
MANE Select: NM_001106
dbSNP: rs1470129412
Type: single nucleotide variant
Location: chr3:38454344 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB

Full ACVR2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

heterotaxy, visceral, 4, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACVR2B c.*4984T>C Uncertain significance ★★ same condition
ACVR2B c.*9473T>C Uncertain significance ★★ same condition
ACVR2B p.Arg161Trp Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg163His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg21His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg309His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg482Gln Uncertain significance ★★ ⚠ same condition
ACVR2B p.Gln246His 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/acvr2b-p-leu8phe (accessed [today's date]).

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