Is COIL p.Val145Ile (c.433G>A) pathogenic?

COIL p.Val145Ile (c.433G>A) is classified Benign in COIL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-02-23). AlphaMissense: likely benign (0.0748); Common (popmax 19.9%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about COIL p.Val145Ile (c.433G>A)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

COIL p.Val145Ile

Q: How common is COIL p.Val145Ile (c.433G>A) in the general population?

COIL p.Val145Ile (c.433G>A) is common (popmax 19.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.433G>A · rs61731978 · VCV1243158

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.9%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.82	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 0.32	GERP -0.62
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.47 · regional, not allelic
Overall
CADD	11.58	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 19.9% Admixed American · 11,928/59,972 alleles

Filtering AF 19.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.5%

Overall 11.8% 191,215/1,613,790 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	21.6%	5
Admixed Americangrpmax	19.9%	5
Finnishnot grpmax-eligible	17.7%	6
South Asian	12.9%	8
European (non-Finnish)	12.2%	8
Remaining individualsnot grpmax-eligible	10.7%	9
Ashkenazi Jewishnot grpmax-eligible	8.32%	12
Middle Eastern	7.23%	14
African / African-American	2.44%	41
East Asian	1.09%	92

Amish 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: COIL
Protein: p.Val145Ile
Coding: c.433G>A
MANE Select: NM_004645
dbSNP: rs61731978
Type: single nucleotide variant
Location: chr17:56950809 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.46
Residue 145: the 'disordered' region

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

Similar variants

COIL p.Glu278= Benign ★★ same type
COIL p.Ala362Ser Uncertain significance ★ ⚠ same type
COIL p.Ala69Thr Uncertain significance ★ ⚠ same type
COIL p.Arg112Trp Uncertain significance ★ ⚠ same type
COIL p.Arg352His Uncertain significance ★ ⚠ same type
COIL p.Arg352Leu Uncertain significance ★ ⚠ same type
COIL p.Arg369Cys Uncertain significance ★ ⚠ same type
COIL p.Arg410Gln 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/coil-p-val145ile (accessed [today's date]).

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