Is GDF6 p.Pro75Arg (c.224C>G) pathogenic?

GDF6 p.Pro75Arg (c.224C>G) is classified Uncertain significance in GDF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0671); Very rare (popmax 0.00167%, amr); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Pro75Arg (c.224C>G)?

GDF6 p.Pro75Arg (c.224C>G) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Pro75Arg (c.224C>G) in the general population?

GDF6 p.Pro75Arg (c.224C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GDF6 p.Pro75Arg (c.224C>G)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

GDF6 p.Pro75Arg

c.224C>G · rs1378920942 · VCV1058818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microphthalmia, isolated, with coloboma 6

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	14.18	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,954 alleles

Overall 0.000124% 2/1,613,010 alleles · very rare exomes 1/1,460,804 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,954
European (non-Finnish)	8.48e-05%	1,179,554

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.Pro75Arg
Coding: c.224C>G
MANE Select: NM_001001557
dbSNP: rs1378920942
Type: single nucleotide variant
Location: chr8:96160469 (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.Pro75Thr Uncertain significance ★ ⚠ same residue
GDF6 p.Pro75= Likely benign ★ 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-pro75arg (accessed [today's date]).

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