Is GDF6 p.Pro320= (c.960G>A) pathogenic?

GDF6 p.Pro320= (c.960G>A) is classified Likely benign in GDF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). Very rare (popmax 0.00602%, eas); Associated with isolated microphthalmia 4.

What condition is associated with GDF6 p.Pro320= (c.960G>A)?

GDF6 p.Pro320= (c.960G>A) is associated with isolated microphthalmia 4, Klippel-Feil syndrome 1, autosomal dominant, microphthalmia, isolated, with coloboma 6 (ClinVar).

How common is GDF6 p.Pro320= (c.960G>A) in the general population?

GDF6 p.Pro320= (c.960G>A) is very rare (popmax 0.00602%, eas) (gnomAD).

GDF6 p.Pro320=

c.960G>A · rs536011360 · VCV2929811

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00602%, eas)

Conditions

isolated microphthalmia 4

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 -0.26	GERP -2.1, phastCons 0.096
Overall
CADD	7.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00602% East Asian · 2/33,240 alleles

Filtering AF 0.000996% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000373%

Overall 0.000287% 4/1,392,528 alleles · very rare exomes 3/1,241,328 · genomes 1/151,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00602%	16,620
Remaining individualsnot grpmax-eligible	0.0019%	52,494
European (non-Finnish)	9.27e-05%	1,079,234

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.Pro320=
Coding: c.960G>A
MANE Select: NM_001001557
dbSNP: rs536011360
Type: single nucleotide variant
Location: chr8:96144971 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 320: the 'disordered' region

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

Disease context

isolated microphthalmia 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Klippel-Feil syndrome 1, autosomal dominant microphthalmia, isolated, with coloboma 6 Leber congenital amaurosis 17

Similar variants

GDF6 p.Pro320Ala Uncertain significance ★ ⚠ same residue
GDF6 p.Pro320Arg Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro320 (accessed [today's date]).

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