Is GDF6 p.Ser284= (c.852C>G) pathogenic?

GDF6 p.Ser284= (c.852C>G) is classified Benign/Likely benign in GDF6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.88%, afr); Associated with Klippel-Feil syndrome 1, autosomal dominant.

What condition is associated with GDF6 p.Ser284= (c.852C>G)?

GDF6 p.Ser284= (c.852C>G) is associated with Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4, microphthalmia, isolated, with coloboma 6 (ClinVar).

How common is GDF6 p.Ser284= (c.852C>G) in the general population?

GDF6 p.Ser284= (c.852C>G) is low-frequency (popmax 1.88%, afr) (gnomAD).

GDF6 p.Ser284=

c.852C>G · rs74498875 · VCV364046

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.88%, afr)

Conditions

Klippel-Feil syndrome 1, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.16	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.024	GERP -0.52, phastCons 0.6
Overall
CADD	6.478	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.88% African / African-American · 1,314/69,926 alleles

Filtering AF 1.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.76%

Overall 0.0977% 1,476/1,511,240 alleles · low-frequency exomes 630/1,359,172 · genomes 846/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.88%	53
Remaining individualsnot grpmax-eligible	0.139%	720
Admixed American	0.129%	774
Middle Eastern	0.0577%	1,732
South Asian	0.00127%	78,620
European (non-Finnish)	0.00114%	87,612

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.Ser284=
Coding: c.852C>G
MANE Select: NM_001001557
dbSNP: rs74498875
Type: single nucleotide variant
Location: chr8:96145079 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88

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

Disease context

Klippel-Feil syndrome 1, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated microphthalmia 4 microphthalmia, isolated, with coloboma 6 Leber congenital amaurosis 17

Similar variants

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
GDF6 p.Ala247Glu Uncertain significance ★★ ⚠ same condition
GDF6 p.Arg248Leu 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-ser284 (accessed [today's date]).

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