Is COG4 p.Ala669Val (c.2006C>T) pathogenic?

COG4 p.Ala669Val (c.2006C>T) is classified Likely pathogenic in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). Absent from gnomAD v4.1; Associated with microcephalic osteodysplastic dysplasia, Saul-Wilson type.

What condition is associated with COG4 p.Ala669Val (c.2006C>T)?

COG4 p.Ala669Val (c.2006C>T) is associated with microcephalic osteodysplastic dysplasia, Saul-Wilson type (ClinVar).

How common is COG4 p.Ala669Val (c.2006C>T) in the general population?

COG4 p.Ala669Val (c.2006C>T) is absent from gnomAD v4.1 (gnomAD).

COG4 p.Ala669Val

Q: How is Microcephalic osteodysplastic dysplasia, Saul-Wilson type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2006C>T · rs539535604 · VCV3065319

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

microcephalic osteodysplastic dysplasia, Saul-Wilson type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.09	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COG4
Protein: p.Ala669Val
Coding: c.2006C>T
MANE Select: NM_015386
dbSNP: rs539535604
Type: single nucleotide variant
Location: chr16:70481864 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB
Residue 669: an α-helix; the 'd domain' region

Full COG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephalic osteodysplastic dysplasia, Saul-Wilson type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Microcephalic osteodysplastic dysplasia, Saul-Wilson type (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

COG4 p.Ala669Pro Likely pathogenic same residue
COG4 p.Glu614Ter Pathogenic ★★ same condition
COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Gly516Arg Pathogenic ★★ same condition
COG4 p.Ala544Val Uncertain significance ★★ same condition
COG4 p.Pro12Leu Uncertain significance ★★ same condition
COG4 p.Thr699Ala Uncertain significance ★★ same condition
COG4 c.1482-25T>C Benign ★★ 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/cog4-p-ala669val (accessed [today's date]).

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