Is GDF6 p.Phe290= (c.870C>T) pathogenic?

GDF6 p.Phe290= (c.870C>T) is classified Benign/Likely benign in GDF6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Rare (popmax 0.28%, mid); Associated with Klippel-Feil syndrome 1, autosomal dominant.

What condition is associated with GDF6 p.Phe290= (c.870C>T)?

GDF6 p.Phe290= (c.870C>T) is associated with Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4, microphthalmia, isolated, with coloboma 6 (ClinVar).

How common is GDF6 p.Phe290= (c.870C>T) in the general population?

GDF6 p.Phe290= (c.870C>T) is rare (popmax 0.28%, mid) (gnomAD).

GDF6 p.Phe290=

c.870C>T · rs765928590 · VCV364045

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Conditions

Klippel-Feil syndrome 1, autosomal dominant

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 2.5	GERP -1.9, phastCons 1
Overall
CADD	6.308	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.28% Middle Eastern · 14/4,998 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.136%

Overall 0.01% 150/1,499,938 alleles · rare exomes 140/1,347,998 · genomes 10/151,940 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	357
South Asian	0.0194%	5,141
Remaining individualsnot grpmax-eligible	0.0156%	6,427
European (non-Finnish)	0.00962%	10,394
Admixed American	0.00414%	24,131
African / African-American	0.00143%	69,724

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.Phe290=
Coding: c.870C>T
MANE Select: NM_001001557
dbSNP: rs765928590
Type: single nucleotide variant
Location: chr8:96145061 (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 p.Phe290Leu Uncertain significance ★ ⚠ 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
GDF6 p.Ala247Glu 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-phe290 (accessed [today's date]).

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