Is ACVR2B p.Ser423= (c.1269G>A) pathogenic?

ACVR2B p.Ser423= (c.1269G>A) is classified Conflicting classifications of pathogenicity in ACVR2B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-23). Ultra-rare (popmax 0.0231%, nfe); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Ser423= (c.1269G>A)?

ACVR2B p.Ser423= (c.1269G>A) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Ser423= (c.1269G>A) in the general population?

ACVR2B p.Ser423= (c.1269G>A) is ultra-rare (popmax 0.0231%, nfe) (gnomAD).

ACVR2B p.Ser423=

c.1269G>A · rs146067304 · VCV414876

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, nfe)

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.1
Overall
CADD	0.074	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% European (non-Finnish) · 273/1,179,914 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.0185% 299/1,612,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0231%	4,322
Middle Eastern	0.0175%	5,718
African / African-American	0.0134%	7,464
Remaining individualsnot grpmax-eligible	0.0112%	8,916
Admixed American	0.00668%	14,968
Finnishnot grpmax-eligible	0.00313%	31,993
South Asian	0.0022%	45,446

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.Ser423=
Coding: c.1269G>A
MANE Select: NM_001106
dbSNP: rs146067304
Type: single nucleotide variant
Location: chr3:38482485 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 423: the protein kinase domain

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-ser423 (accessed [today's date]).

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