Is GDF5 p.Pro154= (c.462C>A) pathogenic?

GDF5 p.Pro154= (c.462C>A) is classified Benign/Likely benign in GDF5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). Rare (popmax 0.777%, afr); Associated with brachydactyly.

What condition is associated with GDF5 p.Pro154= (c.462C>A)?

GDF5 p.Pro154= (c.462C>A) is associated with brachydactyly, acromesomelic dysplasia 2A, acromesomelic dysplasia 2C, Hunter-Thompson type (ClinVar).

How common is GDF5 p.Pro154= (c.462C>A) in the general population?

GDF5 p.Pro154= (c.462C>A) is rare (popmax 0.777%, afr) (gnomAD).

GDF5 p.Pro154=

c.462C>A · rs150686636 · VCV193119

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.777%, afr)

Conditions

brachydactyly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Overall
CADD	9.185	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.777% African / African-American · 583/75,030 alleles

Filtering AF 0.725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.704%

Overall 0.0425% 686/1,614,100 alleles · rare exomes 341/1,461,836 · genomes 345/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.777%	129
Remaining individualsnot grpmax-eligible	0.0784%	1,276
Middle Eastern	0.0495%	2,021
Admixed American	0.0333%	3,001
European (non-Finnish)	0.00254%	39,333
South Asian	0.0011%	91,080

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.Pro154=
Coding: c.462C>A
MANE Select: NM_000557
dbSNP: rs150686636
Type: single nucleotide variant
Location: chr20:35437467 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.04 · 15 PDB
Residue 154: the 'disordered' region

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

Disease context

brachydactyly — 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 multiple synostoses syndrome 2

Similar variants

GDF5 p.Pro154Leu Uncertain significance ★ ⚠ same residue
GDF5 p.Pro154Ser Likely benign ★ 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

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-pro154 (accessed [today's date]).

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