Is GDF6 p.Ala172= (c.516G>T) pathogenic?

GDF6 p.Ala172= (c.516G>T) is classified Likely benign in GDF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). Very rare (popmax 0.00672%, eas); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Ala172= (c.516G>T)?

GDF6 p.Ala172= (c.516G>T) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Ala172= (c.516G>T) in the general population?

GDF6 p.Ala172= (c.516G>T) is very rare (popmax 0.00672%, eas) (gnomAD).

GDF6 p.Ala172=

c.516G>T · VCV3758596

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00672%, eas)

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 0.78	GERP -0.56, phastCons 1
Overall
CADD	11.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00672% East Asian · 3/44,634 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000315% 5/1,587,928 alleles · very rare exomes 4/1,435,686 · genomes 1/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00672%	14,878
Admixed American	0.00172%	58,302
European (non-Finnish)	8.51e-05%	1,174,990

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.Ala172=
Coding: c.516G>T
MANE Select: NM_001001557
Type: single nucleotide variant
Location: chr8:96145415 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.88

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 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-ala172 (accessed [today's date]).

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