Is GDF6 p.Ala82= (c.246G>A) pathogenic?

GDF6 p.Ala82= (c.246G>A) is classified Likely benign in GDF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). Very rare (popmax 8.48e-05%, nfe); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Ala82= (c.246G>A)?

GDF6 p.Ala82= (c.246G>A) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Ala82= (c.246G>A) in the general population?

GDF6 p.Ala82= (c.246G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

GDF6 p.Ala82=

c.246G>A · rs770548453 · VCV2017998

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

microphthalmia, isolated, with coloboma 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -2.7
Overall
CADD	5.775	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,800 alleles

Overall 6.2e-05% 1/1,613,716 alleles · very rare exomes 1/1,461,392 · genomes 0/152,324 · 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: GDF6
Protein: p.Ala82=
Coding: c.246G>A
MANE Select: NM_001001557
dbSNP: rs770548453
Type: single nucleotide variant
Location: chr8:96160447 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 82: the 'disordered' region

Full GDF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microphthalmia, isolated, with coloboma 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Klippel-Feil syndrome 1, autosomal dominant isolated microphthalmia 4 Leber congenital amaurosis 17

Similar variants

GDF6 p.Ala82Glu Uncertain significance ★ ⚠ same residue
GDF6 p.Ala82Val Benign ★ same residue
GDF6 c.*268G>C Uncertain significance ★★ same condition
GDF6 c.*273C>T Uncertain significance ★★ same condition
GDF6 c.*274T>C Uncertain significance ★★ same condition
GDF6 p.Ala199Thr Uncertain significance ★★ ⚠ same condition
GDF6 p.Ala199Val Uncertain significance ★★ ⚠ same condition
GDF6 p.Ala242Thr 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/gdf6-p-ala82 (accessed [today's date]).

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