Is COG7 p.Ser25Phe (c.74C>T) pathogenic?

COG7 p.Ser25Phe (c.74C>T) is classified Uncertain significance in COG7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely benign (0.213); Very rare (popmax 0.00833%, amr); Associated with COG7-congenital disorder of glycosylation.

What condition is associated with COG7 p.Ser25Phe (c.74C>T)?

COG7 p.Ser25Phe (c.74C>T) is associated with COG7-congenital disorder of glycosylation (ClinVar).

How common is COG7 p.Ser25Phe (c.74C>T) in the general population?

COG7 p.Ser25Phe (c.74C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

How is COG7-CDG inherited?

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

What do computational predictors say about COG7 p.Ser25Phe (c.74C>T)?

AlphaMissense predicts likely benign (score 0.213) — an in-silico prediction, not a clinical call.

COG7 p.Ser25Phe

c.74C>T · rs752403903 · VCV2148499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG7-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.213	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -9.23	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 64 kb · p 0.033 · regional, not allelic
Overall
CADD	25.9	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 0.00833% Admixed American · 5/60,010 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00285% 46/1,613,968 alleles · very rare exomes 45/1,461,740 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00305%	32,778
Finnishnot grpmax-eligible	0.00156%	63,972

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: COG7
Protein: p.Ser25Phe
Coding: c.74C>T
MANE Select: NM_153603
dbSNP: rs752403903
Type: single nucleotide variant
Location: chr16:23452921 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.77

Full COG7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG7-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG7-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG7 c.318+1G>A Likely pathogenic ★★ same condition
COG7 p.Ala606Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
COG7 p.Arg444Ter Pathogenic/Likely pathogenic ★★ same condition
COG7 c.1475+4G>A Uncertain significance ★★ same condition
COG7 p.Ala194Val Uncertain significance ★★ ⚠ same condition
COG7 p.Ala222Thr Uncertain significance ★★ ⚠ same condition
COG7 p.Ala29Val Uncertain significance ★★ ⚠ same condition
COG7 p.Ala325Thr 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/cog7-p-ser25phe (accessed [today's date]).

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