Is GDF2 p.Val380Ala (c.1139T>C) pathogenic?

GDF2 p.Val380Ala (c.1139T>C) is classified Conflicting classifications of pathogenicity in GDF2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4706); Ultra-rare (popmax 0.0812%, sas); Associated with telangiectasia, hereditary hemorrhagic, type 5.

What condition is associated with GDF2 p.Val380Ala (c.1139T>C)?

GDF2 p.Val380Ala (c.1139T>C) is associated with telangiectasia, hereditary hemorrhagic, type 5 (ClinVar).

How common is GDF2 p.Val380Ala (c.1139T>C) in the general population?

GDF2 p.Val380Ala (c.1139T>C) is ultra-rare (popmax 0.0812%, sas) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GDF2 p.Val380Ala (c.1139T>C)?

AlphaMissense predicts ambiguous (score 0.4706) — an in-silico prediction, not a clinical call.

GDF2 p.Val380Ala

c.1139T>C · rs567200323 · VCV424503

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4706 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0812%, sas)

Conditions

telangiectasia, hereditary hemorrhagic, type 5

Computational evidence

Protein change
AlphaMissense	0.4706	ambiguous
SaProt	LLR -7.64	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,112 bp · p 0.16 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0812% South Asian · 74/91,080 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0608%

Overall 0.00489% 79/1,613,914 alleles · ultra-rare exomes 72/1,461,592 · genomes 7/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0812%	1,231
Remaining individualsnot grpmax-eligible	0.008%	12,499

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.Val380Ala
Coding: c.1139T>C
MANE Select: NM_016204
dbSNP: rs567200323
Type: single nucleotide variant
Location: chr10:47325633 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.79 · 20 PDB
Residue 380: an α-helix

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

Disease context

telangiectasia, hereditary hemorrhagic, type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

GDF2 p.Val380= Likely benign ★ same residue
GDF2 p.Arg110Gln Likely pathogenic ★★ same condition
GDF2 p.Gln26Ter Pathogenic ★★ same condition
GDF2 p.Glu355Ter Pathogenic/Likely pathogenic ★★ same condition
GDF2 p.Trp214Ter Pathogenic/Likely pathogenic ★★ same condition
GDF2 p.Val423Met Pathogenic/Likely pathogenic ★★ same condition
GDF2 p.Ala105Gly Uncertain significance ★★ ⚠ same condition
GDF2 p.Arg213Cys 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/gdf2-p-val380ala (accessed [today's date]).

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