Is BMP4 p.Ile178Arg (c.533T>G) pathogenic?

BMP4 p.Ile178Arg (c.533T>G) is classified Likely pathogenic in BMP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.9948); Absent from gnomAD v4.1; Associated with microphthalmia with brain and digit anomalies.

What condition is associated with BMP4 p.Ile178Arg (c.533T>G)?

BMP4 p.Ile178Arg (c.533T>G) is associated with microphthalmia with brain and digit anomalies (ClinVar).

How common is BMP4 p.Ile178Arg (c.533T>G) in the general population?

BMP4 p.Ile178Arg (c.533T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMP4 p.Ile178Arg (c.533T>G)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

BMP4 p.Ile178Arg

c.533T>G · VCV4813345

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microphthalmia with brain and digit anomalies

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic ✓ concordant with ClinVar · top 10% in BMP4
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -16.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,588 bp · p 0.035 · regional, not allelic
Overall
CADD	28.0	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: BMP4
Protein: p.Ile178Arg
Coding: c.533T>G
MANE Select: NM_001202
Type: single nucleotide variant
Location: chr14:53950726 (GRCh38)
Gene constraint: LOEUF 0.258 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.12

Full BMP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microphthalmia with brain and digit anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP4 p.Ile178Val Uncertain significance ★ ⚠ same residue
BMP4 p.Arg198Ter Pathogenic ★★ same condition
BMP4 p.Arg113Gln Uncertain significance ★★ ⚠ same condition
BMP4 p.Arg159Trp Uncertain significance ★★ ⚠ same condition
BMP4 p.Arg162Trp Uncertain significance ★★ ⚠ same condition
BMP4 p.Arg177His Uncertain significance ★★ ⚠ same condition
BMP4 p.Arg211Gln Uncertain significance ★★ ⚠ same condition
BMP4 p.Arg223His 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/bmp4-p-ile178arg (accessed [today's date]).

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