Is COTL1 p.Thr66Ile (c.197C>T) pathogenic?

COTL1 p.Thr66Ile (c.197C>T) is classified Uncertain significance in COTL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-28). AlphaMissense: likely pathogenic (0.8298); Ultra-rare (popmax 0.0766%, amr).

How common is COTL1 p.Thr66Ile (c.197C>T) in the general population?

COTL1 p.Thr66Ile (c.197C>T) is ultra-rare (popmax 0.0766%, amr) (gnomAD).

What do computational predictors say about COTL1 p.Thr66Ile (c.197C>T)?

AlphaMissense predicts likely pathogenic (score 0.8298) — an in-silico prediction, not a clinical call.

COTL1 p.Thr66Ile

c.197C>T · VCV3835683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8298 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0766%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8298	likely pathogenic
REVEL	0.251	benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.19 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0766% Admixed American · 46/60,014 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00322% 52/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0766%	1,305
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,801
European (non-Finnish)	0.000339%	295,003

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.Thr66Ile
Coding: c.197C>T
MANE Select: NM_021149
Type: single nucleotide variant
Location: chr16:84590226 (GRCh38)
Gene constraint: LOEUF 1.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.77 · 6 PDB
Residue 66: a β-strand; the adf-h domain; the 'flexible and important for f-actin binding' region

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-thr66ile (accessed [today's date]).

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