Is GDF6 p.Asp411= (c.1233C>T) pathogenic?

GDF6 p.Asp411= (c.1233C>T) is classified Likely benign in GDF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-17). Very rare (popmax 0.00667%, amr); Associated with Klippel-Feil syndrome 1, autosomal dominant.

What condition is associated with GDF6 p.Asp411= (c.1233C>T)?

GDF6 p.Asp411= (c.1233C>T) is associated with Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4, microphthalmia, isolated, with coloboma 6 (ClinVar).

How common is GDF6 p.Asp411= (c.1233C>T) in the general population?

GDF6 p.Asp411= (c.1233C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

GDF6 p.Asp411=

c.1233C>T · rs774375234 · VCV364043

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

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	0.065	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -3.9, phastCons 0.99
Overall
CADD	5.761	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,014 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00192% 31/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
Admixed Americangrpmax	0.00667%	15,004
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,880
European (non-Finnish)	0.00136%	73,753
African / African-American	0.00133%	74,926

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp411=
Coding: c.1233C>T
MANE Select: NM_001001557
dbSNP: rs774375234
Type: single nucleotide variant
Location: chr8:96144698 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 411: a disulfide bond

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-asp411 (accessed [today's date]).

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