Is GDF6 p.Ser312= (c.936G>C) pathogenic?

GDF6 p.Ser312= (c.936G>C) is classified Benign/Likely benign in GDF6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 4.17%, nfe); Associated with Leber congenital amaurosis 17.

What condition is associated with GDF6 p.Ser312= (c.936G>C)?

GDF6 p.Ser312= (c.936G>C) is associated with Leber congenital amaurosis 17, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Ser312= (c.936G>C) in the general population?

GDF6 p.Ser312= (c.936G>C) is low-frequency (popmax 4.17%, nfe) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GDF6 p.Ser312=

c.936G>C · rs148861809 · VCV256851

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.17%, nfe)

Conditions

Leber congenital amaurosis 17

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 -4.8	GERP -2.9
Overall
CADD	1.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.17% European (non-Finnish) · 44,527/1,068,986 alleles

Filtering AF 4.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.12%

Overall 3.63% 50,066/1,379,714 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	16.2%	6
European (non-Finnish)grpmax	4.17%	24
Remaining individualsnot grpmax-eligible	3.4%	29
Middle Eastern	3.21%	31
Ashkenazi Jewishnot grpmax-eligible	3.12%	32
Admixed American	2.76%	36
Finnishnot grpmax-eligible	2.06%	49
South Asian	0.924%	108
African / African-American	0.67%	149
East Asian	0.00312%	32,040

Amish 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.Ser312=
Coding: c.936G>C
MANE Select: NM_001001557
dbSNP: rs148861809
Type: single nucleotide variant
Location: chr8:96144995 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 312: the 'disordered' region

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

Disease context

Leber congenital amaurosis 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Klippel-Feil syndrome 1, autosomal dominant isolated microphthalmia 4 microphthalmia, isolated, with coloboma 6

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

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-ser312 (accessed [today's date]).

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