Is COG4 p.Ser714= (c.2142G>A) pathogenic?

COG4 p.Ser714= (c.2142G>A) is classified Benign in COG4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 51.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with microcephalic osteodysplastic dysplasia, Saul-Wilson type.

COG4 p.Ser714=

Q: What condition is associated with COG4 p.Ser714= (c.2142G>A)?

COG4 p.Ser714= (c.2142G>A) is associated with microcephalic osteodysplastic dysplasia, Saul-Wilson type, COG4-congenital disorder of glycosylation (ClinVar).

Q: How common is COG4 p.Ser714= (c.2142G>A) in the general population?

COG4 p.Ser714= (c.2142G>A) is common (popmax 51.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.2142G>A · rs11054 · VCV128810

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 51.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

microcephalic osteodysplastic dysplasia, Saul-Wilson type

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 -1.4	GERP -3.5, phastCons 0.001
Overall
CADD	7.589	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.2% African / African-American · 38,346/74,856 alleles

Filtering AF 50.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.6%

Overall 44.8% 721,462/1,612,166 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	55.2%	2
Finnishnot grpmax-eligible	52.9%	2
African / African-Americangrpmax	51.2%	2
Ashkenazi Jewishnot grpmax-eligible	50.5%	2
European (non-Finnish)	46.3%	2
Remaining individualsnot grpmax-eligible	43.8%	2
Middle Eastern	41.3%	2
Admixed American	37.2%	3
South Asian	27.1%	4
East Asian	26%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COG4
Protein: p.Ser714=
Coding: c.2142G>A
MANE Select: NM_015386
dbSNP: rs11054
Type: single nucleotide variant
Location: chr16:70481452 (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 714: 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

Also linked: COG4-congenital disorder of glycosylation

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

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

COG4 p.Ser714Trp Uncertain significance ★ same residue
COG4 p.Ser714Leu Uncertain significance ★ same residue
COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg733Trp Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Glu614Ter Pathogenic ★★ same condition
COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Gly516Arg Pathogenic ★★ same condition
COG4 p.Ala251Thr 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/cog4-p-ser714 (accessed [today's date]).

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