Is COG5 p.Phe299Leu (c.895T>C) pathogenic?

COG5 p.Phe299Leu (c.895T>C) is classified Benign in COG5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1246); Common (popmax 91.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Phe299Leu (c.895T>C)?

COG5 p.Phe299Leu (c.895T>C) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How is COG5-CDG inherited?

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

What do computational predictors say about COG5 p.Phe299Leu (c.895T>C)?

AlphaMissense predicts likely benign (score 0.1246) — an in-silico prediction, not a clinical call.

COG5 p.Phe299Leu

Q: How common is COG5 p.Phe299Leu (c.895T>C) in the general population?

COG5 p.Phe299Leu (c.895T>C) is common (popmax 91.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.895T>C · rs2269970 · VCV95374

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1246 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 91.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1246	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -7.72	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 8.5	GERP 0.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	19.07	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F330L vs ClinVar F299L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 91.4% African / African-American · 68,542/74,988 alleles

Filtering AF 90.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 90.6%

Overall 54.1% 872,980/1,612,380 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	91.4%	1
East Asian	64.1%	2
Ashkenazi Jewishnot grpmax-eligible	61.9%	2
Amishnot grpmax-eligible	57.7%	2
Remaining individualsnot grpmax-eligible	55.7%	2
Admixed American	53.9%	2
European (non-Finnish)	52.5%	2
Finnishnot grpmax-eligible	49.3%	2
Middle Eastern	48.4%	2
South Asian	40.1%	2

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: COG5
Protein: p.Phe299Leu
Coding: c.895T>C
MANE Select: NM_006348
dbSNP: rs2269970
Type: single nucleotide variant
Location: chr7:107362361 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

Full COG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG5-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG5-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG5 c.1475+1G>A Likely pathogenic ★★ same condition
COG5 c.2295+2T>C Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg205Ter Pathogenic ★★ same condition
COG5 p.Arg283Ter Pathogenic ★★ same condition
COG5 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg690Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg708Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Met1Arg Pathogenic/Likely pathogenic ★★ ⚠ 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/cog5-p-phe299leu (accessed [today's date]).

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