Is GDF5 p.Arg218= (c.652A>C) pathogenic?

GDF5 p.Arg218= (c.652A>C) is classified Benign/Likely benign in GDF5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.2416); Rare (popmax 0.798%, afr); Associated with brachydactyly.

What condition is associated with GDF5 p.Arg218= (c.652A>C)?

GDF5 p.Arg218= (c.652A>C) is associated with brachydactyly, acromesomelic dysplasia 2A, acromesomelic dysplasia 2C, Hunter-Thompson type (ClinVar).

How common is GDF5 p.Arg218= (c.652A>C) in the general population?

GDF5 p.Arg218= (c.652A>C) is rare (popmax 0.798%, afr) (gnomAD).

What do computational predictors say about GDF5 p.Arg218= (c.652A>C)?

AlphaMissense predicts likely benign (score 0.2416) — an in-silico prediction, not a clinical call.

GDF5 p.Arg218=

c.652A>C · rs116467702 · VCV284616

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2416 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.798%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly

Computational evidence

Protein change
AlphaMissense	0.2416	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.23	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 5	GERP 1.5, phastCons 1
Overall
CADD	17.92	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 0.798% African / African-American · 599/75,072 alleles

Filtering AF 0.745% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.724%

Overall 0.042% 677/1,611,442 alleles · rare exomes 343/1,459,114 · genomes 334/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.798%	125
Remaining individualsnot grpmax-eligible	0.0608%	1,644
Admixed American	0.06%	1,667
Middle Eastern	0.0165%	6,062
South Asian	0.0011%	91,086
European (non-Finnish)	0.000169%	589,977

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.Arg218=
Coding: c.652A>C
MANE Select: NM_000557
dbSNP: rs116467702
Type: single nucleotide variant
Location: chr20:35434763 (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

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.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
GDF5 p.Phe9Leu 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-arg218 (accessed [today's date]).

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