Is COIL p.Ser446Pro (c.1336T>C) pathogenic?

COIL p.Ser446Pro (c.1336T>C) is classified Uncertain significance in COIL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2018); Very rare (popmax 0.00695%, nfe).

How common is COIL p.Ser446Pro (c.1336T>C) in the general population?

COIL p.Ser446Pro (c.1336T>C) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about COIL p.Ser446Pro (c.1336T>C)?

AlphaMissense predicts likely benign (score 0.2018) — an in-silico prediction, not a clinical call.

COIL p.Ser446Pro

c.1336T>C · rs141685795 · VCV2220156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2018	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.86	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 1.7	GERP -2, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.47 · regional, not allelic
Overall
CADD	17.48	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 0.00695% European (non-Finnish) · 82/1,179,872 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00521% 84/1,613,754 alleles · very rare exomes 75/1,461,444 · genomes 9/152,310 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,389
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	75,008

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.Ser446Pro
Coding: c.1336T>C
MANE Select: NM_004645
dbSNP: rs141685795
Type: single nucleotide variant
Location: chr17:56949906 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.46
Residue 446: the '2 x 4 aa repeats of s-l-p-a' 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.Val145Ile 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

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-ser446pro (accessed [today's date]).

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