Is COTL1 p.Val56Ile (c.166G>A) pathogenic?

COTL1 p.Val56Ile (c.166G>A) is classified Uncertain significance in COTL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.0616); Ultra-rare (popmax 0.0156%, eas).

How common is COTL1 p.Val56Ile (c.166G>A) in the general population?

COTL1 p.Val56Ile (c.166G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about COTL1 p.Val56Ile (c.166G>A)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

COTL1 p.Val56Ile

c.166G>A · rs776518628 · VCV3076424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -8.30	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 0.36	GERP -2.3, phastCons 0.037
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.19 · regional, not allelic
Overall
CADD	17.66	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 0.0156% East Asian · 7/44,888 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00149% 24/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
African / African-American	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Admixed American	0.00167%	59,980
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000593%	168,529

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.Val56Ile
Coding: c.166G>A
MANE Select: NM_021149
dbSNP: rs776518628
Type: single nucleotide variant
Location: chr16:84590257 (GRCh38)
Gene constraint: LOEUF 1.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.77 · 6 PDB
Residue 56: 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-val56ile (accessed [today's date]).

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