Is COIL p.Asp460His (c.1378G>C) pathogenic?

COIL p.Asp460His (c.1378G>C) is classified Uncertain significance in COIL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.7345); Ultra-rare (popmax 0.0307%, sas).

How common is COIL p.Asp460His (c.1378G>C) in the general population?

COIL p.Asp460His (c.1378G>C) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

What do computational predictors say about COIL p.Asp460His (c.1378G>C)?

AlphaMissense predicts likely pathogenic (score 0.7345) — an in-silico prediction, not a clinical call.

COIL p.Asp460His

c.1378G>C · VCV4231702

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7345 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7345	likely pathogenic
REVEL	0.506	indeterminate
SaProt	LLR -12.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.94, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.47 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0307% South Asian · 28/91,084 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00186% 30/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,253
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Asp460His
Coding: c.1378G>C
MANE Select: NM_004645
Type: single nucleotide variant
Location: chr17:56949743 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.46
Residue 460: the '2 x 4 aa repeats of s-l-p-a' region; the tudor; atypical domain

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-asp460his (accessed [today's date]).

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