Is BMP4 p.Ser74= (c.222C>T) pathogenic?

BMP4 p.Ser74= (c.222C>T) is classified Uncertain significance in BMP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). Very rare (popmax 0.00133%, afr); Associated with microphthalmia with brain and digit anomalies.

What condition is associated with BMP4 p.Ser74= (c.222C>T)?

BMP4 p.Ser74= (c.222C>T) is associated with microphthalmia with brain and digit anomalies, orofacial cleft 11 (ClinVar).

How common is BMP4 p.Ser74= (c.222C>T) in the general population?

BMP4 p.Ser74= (c.222C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

BMP4 p.Ser74=

c.222C>T · VCV3576622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

microphthalmia with brain and digit anomalies

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 4.6	GERP 1.7, phastCons 1
Overall
CADD	12.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,954 alleles

Overall 6.2e-05% 1/1,613,680 alleles · very rare exomes 0/1,461,436 · genomes 1/152,244 · joint denominator

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: BMP4
Protein: p.Ser74=
Coding: c.222C>T
MANE Select: NM_001202
Type: single nucleotide variant
Location: chr14:53952001 (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

Also linked: orofacial cleft 11

Similar variants

BMP4 p.Ser74Gly 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-ser74 (accessed [today's date]).

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