Is GDF6 p.Pro209Ser (c.625C>T) pathogenic?

GDF6 p.Pro209Ser (c.625C>T) is classified Conflicting classifications of pathogenicity in GDF6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.0188%, mid); Associated with microphthalmia, isolated, with coloboma 6.

What condition is associated with GDF6 p.Pro209Ser (c.625C>T)?

GDF6 p.Pro209Ser (c.625C>T) is associated with microphthalmia, isolated, with coloboma 6, Klippel-Feil syndrome 1, autosomal dominant, isolated microphthalmia 4 (ClinVar).

How common is GDF6 p.Pro209Ser (c.625C>T) in the general population?

GDF6 p.Pro209Ser (c.625C>T) is ultra-rare (popmax 0.0188%, mid) (gnomAD).

What do computational predictors say about GDF6 p.Pro209Ser (c.625C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

GDF6 p.Pro209Ser

c.625C>T · rs1368221807 · VCV2927707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microphthalmia, isolated, with coloboma 6

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.46	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 2.3	GERP -3.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	12.92	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0188% Middle Eastern · 1/5,328 alleles

Filtering AF 0.000397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000149%

Overall 0.000725% 10/1,379,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0188%	5,328
Remaining individualsnot grpmax-eligible	0.00335%	29,833
South Asian	0.00239%	41,845
European (non-Finnish)	0.000437%	229,050

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.Pro209Ser
Coding: c.625C>T
MANE Select: NM_001001557
dbSNP: rs1368221807
Type: single nucleotide variant
Location: chr8:96145306 (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 p.Pro209= 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
GDF6 p.Ala242Thr Uncertain significance ★★ ⚠ same condition
GDF6 p.Ala247Glu 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-pro209ser (accessed [today's date]).

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