Is GDF5 p.Arg351Pro (c.1052G>C) pathogenic?

GDF5 p.Arg351Pro (c.1052G>C) is classified Uncertain significance in GDF5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-08). AlphaMissense: likely pathogenic (0.7578); Very rare (popmax 0.0011%, sas).

How common is GDF5 p.Arg351Pro (c.1052G>C) in the general population?

GDF5 p.Arg351Pro (c.1052G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about GDF5 p.Arg351Pro (c.1052G>C)?

AlphaMissense predicts likely pathogenic (score 0.7578) — an in-silico prediction, not a clinical call.

GDF5 p.Arg351Pro

c.1052G>C · rs781264883 · VCV1500712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7578 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7578	likely pathogenic
REVEL	0.709	pathogenic-leaning
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,016 bp · p 0.079 · regional, not allelic
Overall
CADD	29.6	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 0.0011% South Asian · 1/91,082 alleles

Overall 6.2e-05% 1/1,613,756 alleles · very rare exomes 1/1,461,478 · genomes 0/152,278 · 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.Arg351Pro
Coding: c.1052G>C
MANE Select: NM_000557
dbSNP: rs781264883
Type: single nucleotide variant
Location: chr20:35434363 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.04 · 15 PDB

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

Similar variants

GDF5 p.Arg351Gln Uncertain significance ★ ⚠ same residue
GDF5 p.Arg156Ter Pathogenic/Likely pathogenic ★★ same type
GDF5 p.Arg301Ter Pathogenic/Likely pathogenic ★★ ⚠ same type
GDF5 p.Arg380Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
GDF5 p.Cys400Tyr Likely pathogenic ★★ same type
GDF5 p.Gln210Ter Pathogenic/Likely pathogenic ★★ same type
GDF5 p.Glu491Lys Pathogenic ★★ ⚠ same type
GDF5 p.Trp297Ter Pathogenic/Likely pathogenic ★★ same type

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-arg351pro (accessed [today's date]).

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