Is ACVR2B p.Val185Leu (c.553G>T) pathogenic?

ACVR2B p.Val185Leu (c.553G>T) is classified Uncertain significance in ACVR2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0913); Very rare (popmax 8.47e-05%, nfe); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Val185Leu (c.553G>T)?

ACVR2B p.Val185Leu (c.553G>T) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Val185Leu (c.553G>T) in the general population?

ACVR2B p.Val185Leu (c.553G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACVR2B p.Val185Leu (c.553G>T)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

ACVR2B p.Val185Leu

c.553G>T · rs1279855513 · VCV2142192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 10	GERP -0.63, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 290 bp · p 0.72 · regional, not allelic
Overall
CADD	22.5	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 0.000657% 1/152,148 alleles · very rare

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.Val185Leu
Coding: c.553G>T
MANE Select: NM_001106
dbSNP: rs1279855513
Type: single nucleotide variant
Location: chr3:38478405 (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-val185leu (accessed [today's date]).

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