Is GDF6 p.Pro75= (c.225C>T) pathogenic?

GDF6 p.Pro75= (c.225C>T) is classified Likely benign in GDF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). Ultra-rare (popmax 0.025%, amr); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Pro75= (c.225C>T)?

GDF6 p.Pro75= (c.225C>T) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Pro75= (c.225C>T) in the general population?

GDF6 p.Pro75= (c.225C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

GDF6 p.Pro75=

c.225C>T · rs763584976 · VCV1136022

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Conditions

microphthalmia, isolated, with coloboma 6

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 0.71	GERP -2.9, phastCons 1
Overall
CADD	7.316	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/59,978 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00105% 17/1,613,164 alleles · ultra-rare exomes 15/1,460,830 · genomes 2/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,999
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	8.48e-05%	1,179,550

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.Pro75=
Coding: c.225C>T
MANE Select: NM_001001557
dbSNP: rs763584976
Type: single nucleotide variant
Location: chr8:96160468 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88
Residue 75: the 'disordered' region

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

Similar variants

GDF6 p.Pro75Ser Uncertain significance ★★ ⚠ same residue
GDF6 p.Pro75Arg Uncertain significance ★ ⚠ same residue
GDF6 p.Pro75Thr 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

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-pro75 (accessed [today's date]).

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