Is GDF6 p.Leu289Pro (c.866T>C) pathogenic?

GDF6 p.Leu289Pro (c.866T>C) is classified Conflicting classifications of pathogenicity in GDF6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.7785); Rare (popmax 0.278%, afr); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Leu289Pro (c.866T>C)?

GDF6 p.Leu289Pro (c.866T>C) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Leu289Pro (c.866T>C) in the general population?

GDF6 p.Leu289Pro (c.866T>C) is rare (popmax 0.278%, afr) (gnomAD).

What do computational predictors say about GDF6 p.Leu289Pro (c.866T>C)?

AlphaMissense predicts likely pathogenic (score 0.7785) — an in-silico prediction, not a clinical call.

GDF6 p.Leu289Pro

c.866T>C · rs63751220 · VCV8372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7785 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.278%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microphthalmia, isolated, with coloboma 6

Computational evidence

Protein change
AlphaMissense	0.7785	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.57, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.278% African / African-American · 194/69,756 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.234%

Overall 0.0137% 206/1,502,488 alleles · rare exomes 83/1,350,626 · genomes 123/151,862 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.278%	360
Middle Eastern	0.0197%	5,074
Remaining individualsnot grpmax-eligible	0.0121%	8,279
Admixed American	0.00412%	24,288
European (non-Finnish)	0.000176%	567,118

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.Leu289Pro
Coding: c.866T>C
MANE Select: NM_001001557
dbSNP: rs63751220
Type: single nucleotide variant
Location: chr8:96145065 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 289: a UniProt-annotated variant site (in kfs1)

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 multiple synostoses syndrome 4

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-leu289pro (accessed [today's date]).

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