Is COG4 p.Leu14Pro (c.41T>C) pathogenic?

COG4 p.Leu14Pro (c.41T>C) is classified Uncertain significance in COG4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). Ultra-rare (popmax 0.0296%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COG4 p.Leu14Pro (c.41T>C)?

COG4 p.Leu14Pro (c.41T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COG4 p.Leu14Pro (c.41T>C) in the general population?

COG4 p.Leu14Pro (c.41T>C) is ultra-rare (popmax 0.0296%, nfe) (gnomAD).

COG4 p.Leu14Pro

c.41T>C · rs200844029 · VCV2386086

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.238	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.64	GERP 0.56
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	17.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0296% European (non-Finnish) · 349/1,180,024 alleles

Filtering AF 0.027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.024% 387/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0344%	2,907
European (non-Finnish)grpmax	0.0296%	3,381
Middle Eastern	0.0164%	6,082
African / African-American	0.0107%	9,361
Remaining individualsnot grpmax-eligible	0.008%	12,495
Admixed American	0.00167%	59,984
South Asian	0.0011%	91,088

Finnish 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.Leu14Pro
Coding: c.41T>C
MANE Select: NM_015386
dbSNP: rs200844029
Type: single nucleotide variant
Location: chr16:70523503 (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 14: the 'disordered' region; the 'interaction with scfd1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COG4 p.Leu14Met Uncertain significance ★ same residue
COG4 p.Ala251Thr Uncertain significance ★★ same condition
COG4 p.Ala544Val Uncertain significance ★★ same condition
COG4 p.Ala599Thr Uncertain significance ★★ same condition
COG4 p.Arg177Gln Uncertain significance ★★ same condition
COG4 p.Arg198His Uncertain significance ★★ same condition
COG4 p.Arg266Gln Uncertain significance ★★ same condition
COG4 p.Arg702Gln 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-leu14pro (accessed [today's date]).

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