Is GDF2 p.Val75Phe (c.223G>T) pathogenic?

GDF2 p.Val75Phe (c.223G>T) is classified Uncertain significance in GDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-14). AlphaMissense: likely benign (0.117); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with GDF2 p.Val75Phe (c.223G>T)?

GDF2 p.Val75Phe (c.223G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is GDF2 p.Val75Phe (c.223G>T) in the general population?

GDF2 p.Val75Phe (c.223G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about GDF2 p.Val75Phe (c.223G>T)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

GDF2 p.Val75Phe

c.223G>T · VCV4857910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	Δ0.40	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 4.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,112 bp · p 0.16 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,852 alleles · very rare

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.Val75Phe
Coding: c.223G>T
MANE Select: NM_016204
Type: single nucleotide variant
Location: chr10:47322891 (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.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
GDF2 p.Asn259Ser Benign/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-val75phe (accessed [today's date]).

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