Is GDF5 p.Pro161= (c.483G>A) pathogenic?

GDF5 p.Pro161= (c.483G>A) is classified Conflicting classifications of pathogenicity in GDF5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-19). Very rare (popmax 0.00534%, afr); Associated with multiple synostoses syndrome 2.

What condition is associated with GDF5 p.Pro161= (c.483G>A)?

GDF5 p.Pro161= (c.483G>A) is associated with multiple synostoses syndrome 2, acromesomelic dysplasia 2A, acromesomelic dysplasia 2C, Hunter-Thompson type (ClinVar).

How common is GDF5 p.Pro161= (c.483G>A) in the general population?

GDF5 p.Pro161= (c.483G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

GDF5 p.Pro161=

c.483G>A · rs752789551 · VCV897014

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

multiple synostoses syndrome 2

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 -8.5	GERP -5
Overall
CADD	1.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,918 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00124% 20/1,613,916 alleles · very rare exomes 17/1,461,768 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
European (non-Finnish)	0.00127%	78,662
South Asian	0.0011%	91,084

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: GDF5
Protein: p.Pro161=
Coding: c.483G>A
MANE Select: NM_000557
dbSNP: rs752789551
Type: single nucleotide variant
Location: chr20:35437446 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.04 · 15 PDB
Residue 161: the 'disordered' region

Full GDF5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple synostoses syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acromesomelic dysplasia 2A acromesomelic dysplasia 2C, Hunter-Thompson type acromesomelic dysplasia 2B brachydactyly

Similar variants

GDF5 p.Pro161Leu Uncertain significance ★ ⚠ same residue
GDF5 p.Arg301Ter Pathogenic/Likely pathogenic ★★ ⚠ same condition
GDF5 p.Arg380Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
GDF5 p.Cys400Tyr Likely pathogenic ★★ same condition
GDF5 p.Ala76Ser Uncertain significance ★★ ⚠ same condition
GDF5 p.Arg120Trp Uncertain significance ★★ ⚠ same condition
GDF5 p.Asn356Ser Uncertain significance ★★ ⚠ same condition
GDF5 p.Met173Ile 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/gdf5-p-pro161 (accessed [today's date]).

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