Is GDF5 p.Pro101Ser (c.301C>T) pathogenic?

GDF5 p.Pro101Ser (c.301C>T) is classified Conflicting classifications of pathogenicity in GDF5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-23). AlphaMissense: likely benign (0.0676); Ultra-rare (popmax 0.0347%, afr); Associated with Inborn genetic diseases.

What condition is associated with GDF5 p.Pro101Ser (c.301C>T)?

GDF5 p.Pro101Ser (c.301C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GDF5 p.Pro101Ser (c.301C>T) in the general population?

GDF5 p.Pro101Ser (c.301C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about GDF5 p.Pro101Ser (c.301C>T)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

GDF5 p.Pro101Ser

c.301C>T · rs144074930 · VCV2209986

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP -4.7, phastCons 0.003
Regional constraint	o/e 0.93	unconstrained · MANE · 4,016 bp · p 0.079 · regional, not allelic
Overall
CADD	1.874	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

Grpmax group 0.0347% African / African-American · 26/74,924 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00161% 26/1,614,044 alleles · ultra-rare exomes 7/1,461,866 · genomes 19/152,178 · 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: GDF5
Protein: p.Pro101Ser
Coding: c.301C>T
MANE Select: NM_000557
dbSNP: rs144074930
Type: single nucleotide variant
Location: chr20:35437628 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.04 · 15 PDB
Residue 101: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GDF5 p.Pro101Leu Uncertain significance ★ ⚠ same residue
GDF5 p.Pro101= Likely benign ★ same residue
GDF5 p.Trp297Ter Pathogenic/Likely pathogenic ★★ same condition
GDF5 p.Ala76Ser Uncertain significance ★★ ⚠ same condition
GDF5 p.Arg213Gln Uncertain significance ★★ ⚠ same condition
GDF5 p.Arg240Trp Uncertain significance ★★ ⚠ same condition
GDF5 p.Arg281Cys Uncertain significance ★★ ⚠ same condition
GDF5 p.Arg377Leu 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-pro101ser (accessed [today's date]).

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