Is GDF2 p.Ala321= (c.963C>T) pathogenic?

GDF2 p.Ala321= (c.963C>T) is classified Likely benign in GDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). Very rare (popmax 0.00669%, eas); Associated with Cardiovascular phenotype.

What condition is associated with GDF2 p.Ala321= (c.963C>T)?

GDF2 p.Ala321= (c.963C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is GDF2 p.Ala321= (c.963C>T) in the general population?

GDF2 p.Ala321= (c.963C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

GDF2 p.Ala321=

c.963C>T · VCV3281131

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

Cardiovascular phenotype

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 -11	GERP -3.7
Overall
CADD	0.165	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00223% 36/1,613,546 alleles · very rare exomes 34/1,461,374 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00246%	40,691
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00157%	63,532

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: GDF2
Protein: p.Ala321=
Coding: c.963C>T
MANE Select: NM_016204
Type: single nucleotide variant
Location: chr10:47325457 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.79 · 20 PDB

Full GDF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GDF2 p.Ala321Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
GDF2 p.Ala105Gly Uncertain significance ★★ ⚠ same condition
GDF2 p.Arg333Gln Uncertain significance ★★ ⚠ same condition
GDF2 p.Gly247Val Uncertain significance ★★ ⚠ same condition
GDF2 p.Ala105= Likely benign ★★ same condition
GDF2 p.Ala310= Likely benign ★★ same condition
GDF2 p.Ala365= Likely benign ★★ same condition
GDF2 p.Arg319= Likely benign ★★ 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/gdf2-p-ala321 (accessed [today's date]).

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