Is COTL1 p.Glu44Gln (c.130G>C) pathogenic?

COTL1 p.Glu44Gln (c.130G>C) is classified Uncertain significance in COTL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1413); Very rare (popmax 0.000174%, nfe).

How common is COTL1 p.Glu44Gln (c.130G>C) in the general population?

COTL1 p.Glu44Gln (c.130G>C) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about COTL1 p.Glu44Gln (c.130G>C)?

AlphaMissense predicts likely benign (score 0.1413) — an in-silico prediction, not a clinical call.

COTL1 p.Glu44Gln

c.130G>C · VCV4834561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1413	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -9.46	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 3.9	GERP 0.91, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.19 · regional, not allelic
Overall
CADD	22.6	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 0.000174% European (non-Finnish) · 2/1,149,828 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000142% 2/1,404,782 alleles · very rare

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: COTL1
Protein: p.Glu44Gln
Coding: c.130G>C
MANE Select: NM_021149
Type: single nucleotide variant
Location: chr16:84617531 (GRCh38)
Gene constraint: LOEUF 1.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.77 · 6 PDB
Residue 44: a β-strand; the adf-h domain

Full COTL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COTL1 p.Ala109Thr Uncertain significance ★ ⚠ same type
COTL1 p.Ala135Thr Uncertain significance ★ ⚠ same type
COTL1 p.Ala60Ser Uncertain significance ★ ⚠ same type
COTL1 p.Ala69Ser Uncertain significance ★ ⚠ same type
COTL1 p.Arg117Trp Uncertain significance ★ ⚠ same type
COTL1 p.Arg57Gln Uncertain significance ★ ⚠ same type
COTL1 p.Arg63Cys Uncertain significance ★ ⚠ same type
COTL1 p.Arg63Leu Uncertain significance ★ ⚠ same type

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/cotl1-p-glu44gln (accessed [today's date]).

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